Established Risk Factors Research Articles

Association of Visceral Fat Index with Coronary Collateral Circulation in Patients with Coronary Artery Disease

Abstract: Background: Coronary collateral circulation (CCC) is a network of anastomosing channels, established by heart in response to ischemia of myocardium. Hypertension, diabetes mellitus, and BMI are well established risk factors for development of poor CCC. Good CCC minimizes symptoms of angina, reduce the size of infarcts and prevent adverse cardiac events. The current research study was designed to find out the association of visceral adiposity and development of CCC among patients with coronary artery disease. Materials and Methods: The prospective study, conducted in Civil Hospital Karachi, comprised of 270 patients of coronary artery disease. According to the Rentrop Cohen categorization, patients were placed into two groups: the group with good collateral circulation having Rentrop grades i2-3 (n = 140) and the group with poor collateral circulation having Rentrop grades i0-1(n = 130). Rentrop score was determined by angiography. Segmental multi-frequency bioelectrical impedance analyzer was used to determine body fat mass and body muscle mass. Using Omron body fat and weight measurement systems, visceral fat index (VFI) was evaluated to determine the composition of visceral adipose tissue. SPSS was used for data analysis (Version 22). To assess the independent risk factor for poor CCC, logistic regression analysis was used. ROC curve was constructed to assess the efficacy of VFI in identifying CCC. Results: Overall, good collateral circulations were observed in 51.9% (n=140) of CAD patients, whereas poor collateral circulations were ound in 48.1% (n=130) of patients. Poor CCC was significantly associated with hypertension (OR=3, 95%CI= 0.111-8.231, p = .001) and VFI (OR=2, 95%CI= 1.451-3.567, p =.001). ROC analysis revealed a VFI > 9 to be a potential predictor of poor CCC with AUC=0.9, sensitivity of 95.00% and specificity of 86%. Conclusion: The current study concluded that greater VFI and concomitant hypertension considerably increase the likelihood of having poor CCC, therefore, visceral adiposity can be considered as a potential target for preventing poor collateral circulation in patients with established cardiac disease.

O-262 The vaginal and faecal microbiome in women with recurrent pregnancy loss (RPL) before pregnancy according to the reproductive outcome after referral

Abstract Study question Is the vaginal or faecal microbiome different between primary RPL (pRPL) and secondary RPL (sRPL) patients, and is it related to reproductive outcome after referral? Summary answer Before pregnancy, the vaginal microbiome differed between pRPL and sRPL, and the faecal microbiome was altered in those who did not achieve pregnancy after follow-up. What is known already RPL is a heterogeneous condition leaving 50% of the couples without any known risk factors after the initial diagnostic workup. The microbiome of the reproductive tract seems to be an essential factor in women’s health, including pregnancy loss. Only a few studies have investigated the vaginal microbiome in women with RPL and found dysbiosis with a decrease in Lactobacillus crispatus. To our knowledge, the faecal microbiome in women with RPL has never been investigated. Study design, size, duration A prospective cohort study including 106 women referred with unexplained RPL between 04/2018 and 12/2019. Patients were routinely screened for established risk factors as recommended in the ESHRE RPL guideline. Exclusion criteria were >40 years, >1 shared child, the use of antibiotics, antimycotics and antiviral medication within the past two weeks, known chromosomal aberrations and major uterine malformations. Follow-up ranged between 12-31 months. Participants/materials, setting, methods The women were referred with a minimum of three unexplained consecutive pregnancy losses (64 pRPL and 42 sRPL) to the tertiary Recurrent Pregnancy Loss Unit at Copenhagen University Hospital (Rigshospitalet and Hvidovre Hospital), Denmark. Vaginal and faecal samples were collected before pregnancy and shot-gun sequenced on a DNBSEQ-G400 sequencer (MGI) using the high-throughput sequencing set (PE150 1000016952; MGI). Main results and the role of chance The beta diversity in the vaginal samples was significantly different (p = 0.001) between pRPL and sRPL, with Lactobacillus crispatus dominating more women with pRPL compared to sRPL who were dominated by Lactobacillus iners. Overall, twenty-nine patients (27.3% of the cohort) had vaginal dysbiosis defined as < 60% Lactobacillus spp. with no significant difference between pRPL and sRPL (vaginal dysbiosis in 21.8% vs. 35.7%, p = 0.118). During follow-up, 93 (87.7%) patients achieved pregnancy of which 50 (53.8%) resulted in a live birth and 43 (46.2%) in another pregnancy loss. There were no differences in age, BMI, alpha or beta diversity in the vaginal samples between the live birth group and pregnancy loss group. In the live birth group, 11 patients (22.0%) had vaginal dysbiosis compared with 32.1% of the rest of the cohort, p = 0.242. Ninety-three of 106 women collected a faecal sample at home after the first consultation and there was a significant difference in both alpha diversity (p = 0.014), beta diversity (p = 0.05) and richness (p = 0.001) between women who achieved pregnancy compared with those who did not conceive after follow-up. Limitations, reasons for caution Patients with recurrent pregnancy loss constitute a heterogenic population, which underlines the importance of subgroup comparisons such as pRPL and sRPL. Wider implications of the findings These findings underline the role of an altered vaginal and faecal microbiome as a potential risk factor for RPL. In-depth knowledge about the altered microbiome compositions in these patients can contribute to the generation of future treatment strategies and potentially improve patient care. Trial registration number not applicable

Risk factors for raised left ventricular filling pressure by cardiovascular magnetic resonance: prognostic insights from UK Biobank

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Institute for Health and Care Research British Cardiovascular Society. Background Cardiovascular magnetic resonance imaging (CMR) can estimate left ventricular filling pressure (LVFP). The relationship between LVFP, determined by CMR measurements, and established risk factors for cardiovascular disease is unknown. This study quantifies these associations and investigates the prognostic value of CMR-derived LVFP compared to known risk factors for cardiovascular disease. Methods Using data from the UK Biobank prospective observational cohort study, CMR-derived LVFP was calculated using a model incorporating left atrial volume and left ventricular mass. Logistic regression was used to explore the relationships between raised LVFP (≥15mmHg) and typical cardiovascular risk factors. The non-linear relationship between LVFP and age was analysed using ordinary least squares regression and a restricted cubic spline of age with nine knots. Cox proportional hazards regression was used to analyse the relationships between typical cardiovascular risk factors and CMR-derived LVFP, and outcomes of incident heart failure and major adverse cardiovascular events. Results In this prospective population-based cohort study, 39,163 UK Biobank participants had CMR with adequate image quality. In a multivariable logistic regression model, male sex (OR 4.55, 95% CI 3.85–5.42, p<0.001), age (OR 1.89, 95% CI 1.72 - 2.09, per decade increment, p<0.001), BMI (OR 1.57, 95% CI 1.48–1.67, per SD increment, p<0.001), and hypertension (OR 1.46, 95% CI 1.26–1.68, p<0.001) were associated with increased odds of raised LVFP (Figure 1a). A non-linear regression model of the relationship between age and LVFP, adjusted for all covariables studied, showed little correlation between CMR-derived LVFP and age until 70 years, after which LVFP increased rapidly with age (Figure 2). In multivariable Cox regression models, elevated CMR-derived LVFP was associated with increased hazard of incident heart failure (HR 3.31, 95% CI 1.99–5.49, p<0.001) but not MACE (HR 1.33, 95% CI 0.86–2.07, p = 0.20) (Figure 1b). Conclusions Raised LVFP, as determined using CMR, is independently associated with male sex, age, BMI and hypertension. CMR-derived LVFP is independently associated with incident heart failure. These findings may have implications for clinical risk stratification, targeted population screening strategies and public health measures to reduce the risk of heart failure development.

Frailty in aneurysmal subarachnoid hemorrhage: the risk analysis index.

Few studies have evaluated frailty in the setting of aneurysmal subarachnoid hemorrhage (aSAH) using large-scale data. The risk analysis index (RAI) may be implemented at the bedside or assessed retrospectively, differentiating it from other indices used in administrative registry-based research. Adult aSAH hospitalizations were identified in the National Inpatient Sample (NIS) from 2015 to 2019. Complex samples statistical methods were performed to evaluate the comparative effect size and discriminative ability of the RAI, the modified frailty index (mFI), and the Hospital Frailty Risk Score (HFRS). Poor functional outcome was determined by the NIS-SAH Outcome Measure (NIS-SOM), shown to have high concordance with modified Rankin Scale scores > 2. 42,300 aSAH hospitalizations were identified in the NIS during the study period. By both ordinal [adjusted odds ratio (aOR) 3.20, 95% confidence interval (CI) 3.05, 3.36, p < 0.001] and categorical stratification [frail aOR 3.59, 95% CI 3.39, 3.80, p < 0.001; severely frail aOR 6.67, 95% CI 5.78, 7.69, p < 0.001], the RAI achieved the largest effect sizes for NIS-SOM in comparison with the mFI and HFRS. Discrimination of the RAI for NIS-SOM in high-grade aSAH was significantly greater than that of the HFRS (c-statistic 0.651 vs. 0.615). The mFI demonstrated the lowest discrimination in both high-grade and normal-grade patients. A combined Hunt and Hess-RAI model (c-statistic 0.837, 95% CI 0.828, 0.845) for NIS-SOM achieved significantly greater discrimination than both the combined models for mFI and HFRS (p < 0.001). The RAI was robustly associated with poor functional outcomes in aSAH independent of established risk factors.

Are higher odontogenic infection severity scores associated with difficult intubations?

This study aimed to determine if there is a relation between odontogenic infection severity score (OISS) and difficult intubation at the time of surgical treatment for severe odontogenic infections (SOI). A secondary goal of this study was to determine the utility of OISS as a predictor of difficult intubations. This retrospective cohort study was composed of consecutive patients admitted and surgically treated in the operating room (OR) for SOIs. Patients with an OISS ≥ 5 were designated as Group 1 and < 5 Group 2. There was a statistically significant difference in difficult intubations between the two groups (p = 0.018). Patients with an OISS ≥ 5 were nearly four times more likely to be difficult intubations compared to patients with an OISS < 5 (OR 3.70, 95% CI 1.19-11.45). When OISS ≥ 5 was used to predict difficult intubation, the sensitivity was 69%, the specificity was 63%, the positive predictive value was 23%, and the negative predictive value was 93%. OISS ≥ 5 was associated with a higher prevalence of difficult intubations compared to an OISS < 5. OISS may provide clinically relevant data that can be used with established risk factors, laboratory values, and clinical judgment.

Substance use under a restrictive and prohibitive policy regime in secondary schools in Uganda: The convergence of motives, contexts and student characteristics

Drug use among young people is increasing in Africa. To prevent drug use, it is essential to understand the motivations, environments, and characteristics of users. Although there are established risk factors for drug use, little is known about the reasons why adolescents and young people take drugs. This study investigated the reasons given by a sample of secondary school pupils for using drugs and other substances, specifically, how adolescents circumvent the restrictive and prohibitive policy regime and rationalize and account for drug use. This study used a cross-sectional mixed-methods design. For quantitative data, descriptive and regression analyses were run, and for qualitative data, thematic analysis was used. About 13 per cent (n=41) met criteria for moderate to severe drug use. Coping (Mean = 4.13, SD 0.89), social (Mean = 3.71, SD 0.97), and enhancement (Mean = 3.09, SD 0.92) motives were highly endorsed as motives for drug use. The extent to which motives predicted drug use ranged from β = 0.55 (95% CI: 0.39, 0.72) for coping to β = 0.18 (95% CI: 0.08, 0.28) for expansion motives. Students employed ingenious and frequently risky ways to circumvent the rigorous and prohibitive regulatory regimes governing drug use in schools. Academic stress, limited recreational activities, poor stress management, peer influence, poor adult supervision and dysfunctional family backgrounds, all interrelate in complex ways with motives, contexts, and student characteristics to create a conducive environment for the rationalisation, medicalisation, and veneration of drug use. Further research on contexts, motives and characteristics of adolescents that shape drug use is needed.

The added value of (1,3)-β-D-glucan for the diagnosis of Invasive Candidiasis in ICU patients: a prospective cohort study

PurposeBeta-D-Glucan (BDG) testing has been suggested to support the diagnosis of candidemia and invasive candidiasis. The actual benefit in critically ill high-risk patients in intensive care units (ICU) has not been verified so far.MethodsIn ICU patients receiving empirical echinocandin treatment for suspected invasive candidiasis (IC), serial BDG testing using the Fujifilm Wako Beta-Glucan Test was performed, starting on the first day of echinocandin administration and every 24-48 h afterwards. Diagnostic accuracy was determined for single testing and serial testing strategies using a range of cut-off values. In addition, we compared the added value of these testing strategies when their results were introduced as additional predictors into a multivariable logistic regression model controlling for established risk factors of IC.ResultsA total of 174 ICU patients, forty-six of which (25.7%) classified as cases of IC, were included in our study. Initial BDG testing showed moderate sensitivity (74%, 95%CI 59–86%) and poor specificity (45%, 95% CI 36–54%) for IC which could hardly be improved by follow-up testing. While raw BDG values or test results obtained with very high thresholds improved the predictive performance of our multivariable logistic regression model for IC, neither single nor serial testing with the manufacturer-proposed low-level cut-off showed substantial benefit.ConclusionsIn our study of critically ill intensive care patients at high risk for candidemia or invasive candidiasis, diagnostic accuracy of BDG testing was insufficient to inform treatment decisions. Improved classification was only achieved for cases with very high BDG values.

#5650 METABOLIC BLOOD BIOMARKER PROFILING FOR CHRONIC KIDNEY DISEASE PREDICTION – EVIDENCE FROM 275,000 INDIVIDUALS IN THE UK BIOBANK

Abstract Background and Aims Early identification of individuals at high risk of developing chronic kidney disease and other chronic conditions is essential for targeted prevention. Here, we assess the utility of metabolic blood biomarkers in predicting the onset of chronic kidney disease in over 250,000 individuals from UK Biobank, beyond established risk factors and polygenic risk scores. Method Circulating blood biomarkers, including lipids, fatty acids, amino acids, glycolysis metabolites and inflammation markers were measured by a low-cost nuclear magnetic resonance (NMR) metabolomics assay in around 275,000 plasma samples from the UK Biobank. During a prospective 10-year follow-up, over 6000 incident chronic kidney disease events were obtained from national health registries. Using multivariable regression modelling, we derived a 10-year risk score for chronic kidney disease onset. We assessed the predictive performance of the biomarker risk score in comparison to standard risk factors (age, sex, prevalent diabetes, body mass index, systolic and diastolic blood pressure, smoking status and use of cholesterol lowering medication), clinical chemistry measurements (HbA1c, LDL and HDL cholesterol, total cholesterol and eGFR) and polygenic risk scores. We evaluated the performance of the risk score in two practical scenarios: in a general population screening setting and in a clinical use case of stratifying kidney disease risk among prevalent type 2 diabetics. We further illustrate applications of the biomarker risk scores in predicting the risk of other chronic diseases, such as cardiovascular outcomes, in general population settings. Results In the general population screening setting, adding the metabolic biomarkers to a simple model of standard risk factors substantially improved the predictive performance, with area under the receiver operating characteristic curve (AUC) increasing from 0.74 to 0.82. When compared to more comprehensive model including also clinical chemistry measurements and polygenic risk scores, the improvements were also significant, albeit more modest, with the AUC increasing from 0.81 to 0.83. Even more substantial gains were observed in a clinical use case scenario of stratifying risk of chronic kidney disease onset among prevalent type 2 diabetics. Among diabetics with mildly to moderately decreased kidney function at the time of blood sampling (eGFR 60-90), adding the metabolic biomarkers in a comprehensive model including standard risk factors, clinical chemistry measurements and polygenic risk scores increased the AUC from 0.60 to 0.70. Conclusion Circulating metabolic biomarkers enhanced the prediction of chronic kidney disease onset beyond standard risk factors and polygenic risk scores. From a translational perspective, this may complement the identification of high-risk individuals in both general population and clinical settings beyond current risk factor assessment, while simultaneously informing on the risk of other chronic diseases.

Associations between higher plasma ferritin and hepcidin levels with liver stiffness in patients with type 2 diabetes: An exploratory study.

Currently, there is no information about the association between circulating levels of ferritin and hepcidin and liver fibrosis in patients with type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD). We enrolled 153 patients with T2DM with no known liver diseases, who consecutively attended our diabetes outpatient service and who underwent liver ultrasonography and liver stiffness measurement (LSM) by vibration-controlled transient elastography (Fibroscan® for the non-invasive assessment of liver fibrosis). Plasma ferritin and hepcidin concentrations were measured with an electrochemiluminescence immunoassay and mass spectrometry-based assay, respectively. After stratification of patients by LSM tertiles [1st tertile median LSM: 3.6 (interquartile range: 3.3-4.0) kPa, 2nd tertile: 5.3 (4.9-5.9) kPa and 3rd tertile: 7.9 (6.7-9.4) kPa], we found that plasma ferritin and hepcidin concentrations increased across LSM tertiles [median ferritin: 68.7 (interquartile range: 25.1-147) vs. 85.8 (48.3-139) vs. 111 (59.3-203) μg/L, p = 0.021; median hepcidin: 2.5 (1.1-5.2) vs. 4.4 (2.5-7.3) vs. 4.1 (1.9-6.8) nmol/L, p = 0.032]. After adjustment for age, sex, diabetes duration, waist circumference, haemoglobin A1c, HOMA-insulin resistance score, triglycerides, haemoglobin, presence of hepatic steatosis on ultrasonography and patatin-like phospholipase domain-containing-3 (PNPLA3) rs738409 genetic variant, higher plasma ferritin levels were associated with greater LSM values (adjusted-odds ratio 2.10, 95% confidence interval 1.23-3.57, p = 0.005). Higher plasma hepcidin levels were also associated with greater LSM values (adjusted-odds ratio 1.90, 95% confidence interval 1.15-3.13, p = 0.013). Higher levels of plasma ferritin and hepcidin were associated with greater NAFLD-related liver fibrosis (assessed by LSM) in patients with T2DM, even after adjustment for established cardiometabolic risk factors, diabetes-related variables and other potential confounders.

#4295 SPECTRUM OF GLOMERULAR AND VASCULAR KIDNEY PATHOLOGY ASSOCIATED WITH MYELOPROLIFERATIVE NEOPLASMS

Abstract Background and Aims Myeloproliferative neoplasms (MPN) are chronic blood disorders defined by an overproduction of clonal, differentiated hematopoietic cells. A high prevalence of chronic kidney disease (CKD) is described in patients with MPN. The glomerular histological pattern of MPN-related kidney disease, MPN-related glomerulopathy (MPN-RG), may not account for the entirety of CKD risk in this population, as it appears to be rare and has mostly been reported in patients with myelofibrosis. The inflammatory and prothrombotic state of clonal blood cells has been linked to a systemic vasculopathy in MPN patients, characterized by thromboses and microvascular disease. Thus, we put forward the hypothesis that intrarenal vessel injury may occur during MPN, and that vascular nephrosclerosis may be a common histological pattern in MPN patients presenting with kidney disease. Method We conducted an exhaustive, retrospective, multicenter study of MPN kidney biopsies in four kidney pathology units. All adult patients with a history of MPN who underwent a kidney biopsy were included. We performed a systematic histological review of glomerular and vascular compartments. MPN-RG was defined as mesangial expansion and negative glomerular immunofluorescence studies, with at least one of the following: mesangial hypercellularity, or features of chronic glomerular thrombotic microangiopathy. Hematopoietic cells were detected using anti-glycophorin C, anti-myeloperoxidase, and anti-factor VIII immunohistochemistry (IHC). Chronic vascular lesions were evaluated using the Banff aah and cv lesion definitions and compared to matched adult native kidney biopsies. We used multivariable logistic regression models to assess determinants of vascular lesions, using the number of antihypertensive drugs as a proxy for hypertension severity. Results We included 47 MPN patients who underwent a kidney biopsy, including 16 patients with chronic myeloid leukemia, 14 with polycythemia vera, 10 with essential thrombocythemia and 7 with primary myelofibrosis. 14 cases (29.8%) met our definition of MPN-RG. MPN-RG was strongly associated with myelofibrosis (primary or secondary, P = 0.021) and poorer ESRD-free survival (P = 0.007). Positive IHC for circulating cells in the glomerular capillaries was not associated with glomerular injury but was positively correlated with blood leukocyte count (P = 0.004). Thirty-three patients (75.0%) had moderate-to-severe arteriosclerosis; 39 patients (84.8%) had moderate-to-severe arteriolar hyalinosis. Multivariable models including 188 control kidney biopsies revealed an association between MPN and chronic kidney vascular damage, which was independent of established risk factors such as age, diabetes mellitus and hypertension (Table 1 and Table 2). Conclusion We demonstrate the strong association between MPN-RG and myelofibrosis and confirm its poor renal prognosis. We argue that the finding of glomerular intracapillary hematopoietic cells should not be considered in the diagnosis of MPN-RG. Most notably, our results show that MPN represent a novel, independent risk factor for vascular nephrosclerosis, and establish a new link between MPN and CKD. These findings raise new hypotheses regarding the pathophysiology of vascular nephrosclerosis in the general population.

The impact of established risk factors for psychosis on the 3-year outcomes

The impact of established risk factors for psychosis on the 3-year outcomes

Multiview Clustering to Identify Novel Kidney Donor Phenotypes for Assessing Graft Survival in Older Transplant Recipients.

Older transplant recipients are at a relatively increased risk of graft failure following transplantation and some of this risk may relate to donor characteristics. Unsupervised clustering using machine learning may be a novel approach to identify donor phenotypes that may then be used to evaluate outcomes for older recipients. Using a cohort of older recipients, the purpose of this study was to A) use unsupervised clustering to identify donor phenotypes and B) determine the risk of death/graft failure for recipients of each donor phenotype. We analyzed a nationally representative cohort of kidney transplant recipients age >65 years captured using the Scientific Registry of Transplant Recipients between 2000-2017. Unsupervised clustering was used to generate phenotypes using donor characteristics inclusive of variables in the kidney donor risk index (KDRI). Cluster assignment was internally validated. Outcomes included all-cause graft failure (including mortality) and delayed graft function (DGF). Differences in the distribution of KDRI scores were also compared across the clusters. All-cause graft failure was compared for recipients of donor kidneys from each cluster using a multivariable Cox-Survival analysis. Overall, 23,558 donors were separated into five clusters. The area under the curve for internal validation of cluster assignment was 0.89. Recipients of donor kidneys from two clusters were found to be at high risk of all-cause graft failure relative to the lowest risk cluster (adjusted hazards ratio 1.86, 95% CI 1.69-2.05 and 1.73, 95% CI 1.61-1.87). Only, one of these high-risk clusters had high proportions of donors with established risk factors (i.e., hypertension, diabetes). KDRI scores were similar for the highest and lowest risk clusters (1.40 [1.18-1.67] and 1.37 [1.15-1.65], respectively). Unsupervised clustering can identify novel donor phenotypes comprised of established donor characteristics that, in turn, may be associated with different risks of graft loss for older transplant recipients.

Role of Epicardial Adipose Tissue Secretome on Cardiovascular Diseases.

Obesity and insulin resistance are associated with the inflamed and defective adipose tissue (AT) phenotype, and are established risk factors for cardiovascular diseases (CVDs). Extracellular vesicles (EVs) are a heterogeneous group of cell-derived lipid membrane vesicles involved in the onset and development of many pathologies, including insulin resistance, diabetes, and CVDs. The inflammation associated with overweight and obesity triggers the transition of the AT secretome from healthy to pathological, with a consequent increased expression of pro-inflammatory mediators. Epicardial adipose tissue (EAT) is a specialized fat depot that surrounds the heart, in direct contact with the myocardium. Recently, the role of EAT in regulating the physiopathology of many heart diseases has been increasingly explored. In particular, the EAT phenotype and derived EVs have been associated with the onset and exacerbation of CVDs. In this review, we will focus on the role of the AT secretome in the case of CVDs, and will discuss the beneficial effects of EVs released by AT as promising therapeutic candidates.

Persistence of SARS-CoV-2 IgG Antibody Response among South African Adults: A Prospective Cohort Study.

This study assesses the durability of severe acute respiratory coronavirus-2 (SARS-CoV-2) anti-nucleocapsid (anti-N) immunoglobulin G (IgG) after infection and examines its association with established risk factors among South African healthcare workers (HCWs). Blood samples were obtained from 390 HCWs with diagnosis of coronavirus disease 2019 (COVID-19) for assay of the SARS-CoV-2 anti-N IgG at two time points (Phase 1 and 2) between November 2020 and February 2021. Out of 390 HCWs with a COVID-19 diagnosis, 267 (68.5%) had detectable SARS-CoV-2 anti-N IgG antibodies at the end of Phase I. These antibodies persisted for 4-5 and 6-7 months in 76.4% and 16.1%, respectively. In the multivariate logistic regression model analysis, Black participants were more likely to sustain SARS-CoV-2 anti-N IgG for 4-5 months. However, participants who were HIV positive were less likely to sustain SARS-CoV-2 anti-N IgG antibodies for 4-5 months. In addition, individuals who were <45 years of age were more likely to sustain SARS-CoV-2 anti-N IgG for 6-7 months. Of the 202 HCWs selected for Phase 2, 116 participants (57.4%) had persistent SARS-CoV-2 anti-N IgG for an extended mean period of 223 days (7.5 months). Findings support the longevity of vaccine responses against SARS-CoV-2 in Black Africans.

Optimizing a Diagnostic Model of Periodontitis by Using Targeted Proteomics.

Periodontitis (PD), a widespread chronic infectious disease, compromises oral health and is associated with various systemic conditions and hematological alterations. Yet, to date, it is not clear whether serum protein profiling improves the assessment of PD. We collected general health data, performed dental examinations, and generated serum protein profiles using novel Proximity Extension Assay technology for 654 participants of the Bialystok PLUS study. To evaluate the incremental benefit of proteomics, we constructed two logistic regression models assessing the risk of having PD according to the CDC/AAP definition; the first one contained established PD predictors, and in addition, the second one was enhanced by extensive protein information. We then compared both models in terms of overall fit, discrimination, and calibration. For internal model validation, we performed bootstrap resampling (n = 2000). We identified 14 proteins, which improved the global fit and discrimination of a model of established PD risk factors, while maintaining reasonable calibration (area under the curve 0.82 vs 0.86; P < 0.001). Our results suggest that proteomic technologies offer an interesting advancement in the goal of finding easy-to-use and scalable diagnostic applications for PD that do not require direct examination of the periodontium.

The long journey of patients with anal carcinoma in a Mexican cohort.

e15504 Background: Yearly 1000 new cases of anal cancer will be diagnosed in the USA, in Mexico this information is limited. Increasing incidence is the reflection of improvements in knowledge of risk factors and diagnostic studies. Female sex, HPV infection, genital warts, number of sexual partners, receptive anal intercourse, smoking and HIV infection are well established risk factors. Methods: We performed a retrospective analysis of patients with pathology-confirmed anal carcinoma treated at an Oncology Reference Center in North-East Mexico from 2010 to 2020. Using the digital database of our center we searched the time passed since debut of symptoms to first medical contact, date of biopsy and first oncology consultation. Results: 81 patients were found in the database from January 2010 to December 2020. Forty-one patients were included in the final analysis, 11 patients where reassessed as rectal cancer and 29 patients only attended one consultation and did not continue follow up. Mean age at diagnosis was 61.4 +/- 13.8 years and 58.5% were women. 69% of patients had an education degree lower than highschool. HIV status was known only in 9.8% as they were living with HIV before the diagnosis of anal cancer was made, contrasting from 63.4% of cases who had unknown status at cancer diagnosis. The time from symptom onset until the patient attended a healthcare provider was a mean of 7.6 months (5 – 1000 days) and 11.4 months (9-1435 days) to receive a diagnosis. Patients had an average delay of 80 days from biopsy result to be evaluated by an oncologist. 44% of patients were initially misdiagnosed as hemorrhoids. None of the female patients had history of recent Pap smear test. 65% of patients had nodal involvement at presentation. Conclusions: There is notable delay between the onset of symptoms and diagnosis of anal cancer. This information is crucial for the general population and all healthcare providers not only oncology related workers. The stigma as well as the cultural barriers associated with this disease may negatively impact the prognosis and quality of life by delaying promptly treatment. Although it is a rare disease, conducting educational campaigns with the intention of improving clinical suspicion and an early recognition may shorten the long journey of patients bearing with anal carcinoma.

The risk of cerebrovascular accidents in colon cancer in the United States: A population-based national study.

e15516 Background: Colon cancer is the 3rd most common cause of cancer death in the United States. However, death rates have been decreasing due to increased uptake of screening and advances in treatment; as a result, there are more than 1.5 million survivors. In addition, cancer as a risk for venous thromboembolism (VTE) is established, and the underlying mechanisms of VTE are shared with arterial thromboembolism. Yet, there is a lack of population-based data to define the risk of cerebrovascular accidents (CVA) in colon cancer. Methods: Retrospectively we analyzed data from a nationwide commercial database (Explorys, IBM) from 1999 to October 2022. It aggregates records from 26 healthcare systems across 50 states with almost 80 million patients. We identified adults over 18 years old with colon cancer and obtained data on risk factors, including sex, age over 65 years, hypertension (HTN), hyperlipidemia (HLD), diabetes mellitus (DM), atrial fibrillation, obesity, and tobacco use. Multivariable logistic regression was used to adjust for the variables collected. All tests were two-sided, and a p-value ≤ 0.05 was considered statistically significant. Results: A population of 69,339,860 was included. Colon cancer was diagnosed in 304,650 (0.4%) and CVA in 237,290 (0.3%). Males made 45%. The colon cancer group, compared to the background population, had a higher prevalence of patients aged over 65 years (66.8% vs. 30.7%), HTN (61% vs. 21.1%), HLD (50.7% vs. 16.9%), DM (31.4% vs. 8.8%), obesity (20.7% vs. 8.0%), tobacco use (12.5% vs. 6.6%) and CVA (5% vs. 0.3%). Multivariable logistic regression of variable studies (Table). Colon cancer was significantly associated with CVA. Conclusions: Our study included over 69 million adults, making it the most extensive population-based study of the risk of CVA in colon cancer in the United States. After adjustment for most established risk factors that may confound the result, colon cancer was associated with a significantly increased risk of CVA, and it was preceded only by HTN. Colon cancer portrayed more risk than atrial fibrillation. Limitations of population-based studies are several, including inaccuracies and miscoding. Our findings suggest that colon cancer survivors and patients with stable disease on treatment may have their prognosis and quality of life jeopardized by CVA. Prospective studies are needed, and management of modifiable risk factors in collaboration with primary care is paramount. [Table: see text]

Risk factors (RF) for poor outcomes in esophageal (EC) and gastric (GC) adenocarcinomas treated with immune-checkpoint inhibitors (ICI).

e16032 Background: There are no established risk factors or toxicity biomarkers for ECs and GCs treated with ICI, even though they are commonly used in current clinical practice. Additionally, the predictive value of programmed death-ligand 1 (PDL1) expression level is questionable. This is a retrospective review of patients with EC or GC treated with ICI at an academic institute to identify RF for poor outcomes. Methods: Patients with EC or GC who received at least one dose of ICI for Stage IV or recurrent disease between 1/1/2015 and 7/31/2021 at the Ohio State University were included in the study. The patients' baseline (BL) characteristics (at the first dose of ICI) were extracted with immune-related adverse events (irAE) details and survival outcomes. Descriptive statistics, Fisher exact test for categorical variables, log-rank test for survival outcomes, and logistic regression modeling for categorical outcomes were conducted using JMP Pro 16 (SAS Institute Inc., Cary, NC). Results: Our cohort included 67 patients (42 EC and 25 GC). The median age was 65 years (range 33-90) with 84% male, 88% Caucasian (4% African American &amp; 8% others), and 93% with distant metastasis (7% recurrent disease). 75% received the first ICI dose in ≥ 3 lines with 4% first line, 41% had a history of radiotherapy (XRT) (22% palliative &amp; 19% neoadjuvant [NA]), and only 9% had chemotherapy combination (CC). Most were microsatellite stable (90%), and PDL1 expression was not available in 39%, negative in 7%, and positive in 53%. Median overall survival (OS) and progression-free survival (PFS) were 5 months (m) (95% confidence interval [CI], 2-8) and 3m (95% CI, 2-4), respectively. Patients with ICI in ≥ 3 lines did worse (vs ≤ 2 lines, 3m vs 12m, respectively, p = 0.01) in OS. Patients with a history of XRT had lower PFS (yes vs no, 2m vs 3m, p = 0.02), but OS was not significantly different. BL white cell count (WBC) (p = 0.002), alkaline phosphatase (ALP) (p = 0.006), total bilirubin (TB) (p = 0.004), thyroid stimulating hormone (TSH) (p = 0.04), and free T4 (p = 0.01) significantly impacted OS, while WBC (p = 0.01), red cell count (RBC) (p = 0.02), platelet count (PLC) (p = 0.04), and absolute lymphocyte count (ALC) (p = 0.01) impacted PFS. RFs positively related to OS and PFS were the line of ICI and CC, while high ALP and prior XRT were negatively related to OS and PFS. Low albumin (p = 0.003) was negatively related to OS-only while primary tumor location (EC, p = 0.04) and prior NA XRT (p = 0.01) were negatively related to PFS-only. Other BL characteristics, including PDL-1 expression (among patients with available values), did not impact outcomes. Only 7% (n = 5) had irAE, and two had ≥ grade 3. Conclusions: Patients with identified RFs (EC primary, prior XRT, NA XRT, and BL labs such as WBC, RBC, PLC, ALP, ALC, albumin, TB, TSH, and free T4) for clinical outcomes should be monitored closely. These associations should be confirmed in larger studies.

Surgical resection based on ontogenetic cancer field theory for cervical cancer: 10-year updated results of the MMR study.

5539 Background: Previously published findings from our center suggest that carcinoma of the cervix propagates within ontogenetic cancer fields, tissue compartments defined by staged morphogenesis. In the MMR study we aimed to determine whether surgical treatment that accounts for stage-associated, ontogenetic cancer fields and their associated lymphoid tissues results in locoregional tumor control without the need for adjuvant radiotherapy. Methods: The Leipzig School Mesometrial Resection Study (MMR study) is an ongoing, prospective, single-center, observational cohort study including patients with primary cervical cancer. All study participants undergo either total or extended mesometrial resection (TMMR or EMMR) and therapeutic lymph node dissection. Because this treatment strategy enables surgical removal of all locoregional at-risk tissues, no adjuvant radiotherapy is necessary, even in the presence of established risk factors. The trial is registered at the German Clinical Trials Register, number DRKS00015171. For this updated analysis, we identified patients in our institutional study database with primary cervical cancer staged IB1 – IIA2 according to the 2009 International Federation of Gynecology and Obstetrics staging system. Using the Kaplan-Meier estimator, we calculated recurrence free and overall survival. Results: Between October 16, 1999, and December 16, 2020, 420 patients were treated per protocol and followed up for a median of 136 months (IQR 77-190). The median age was 42 years (IQR 36-51). 329 patients (78.3%) had stage IB1, 58 (13.8%) stage IB2, 24 (5.7%) stage IIA1 and 9 (2.1%) stage IIA2 disease. Patients had either squamous cell (n = 297, 70.7%), adenocarcinoma (n = 104, 24.8%), adenosquamous (n = 18, 4.3%) or other (n = 1, 0.24%) histology. The nodal status was pN0 in 349 (83.1%) patients and pN1 in 71 (16.9%) of the cases. Clinically occult parametrial involvement was present in 47 (11.2%) patients. 10-year overall survival was 90.2% (95% confidence interval [CI] 87.1-93.4) and recurrence-free survival was 90.6% (95% CI 87.8-93.6). Stratified for lymph node status 10-year overall survival was 91.7% (95% confidence interval [CI] 88.5-95) for pN0 and 83.2% (95% confidence interval [CI] 74.6-92.9) for pN1. Recurrence-free survival was 93.8% (95% CI 91.2-96.5) for pN0 and 75.4% (95% CI 65.9-86.3) for pN1. Conclusions: Despite dispense of adjuvant radiotherapy, patients treated with total or extended mesometrial resection with therapeutic lymph node dissection have excellent survival outcomes. Additional multicenter studies are needed to further investigate and confirm our results. Clinical trial information: DRKS00015171 .

Friendly-user score assessing gut dysbiosis and resistance to immune checkpoint inhibitors (ICI).

103 Background: Accumulating evidence pointed to the impact of the intestinal microbiota on ICI outcomes across various cancers. Although specific gut microbial species have been associated with beneficial responses ( i.e. Akkermansia muciniphila (Akk)), no consensus exists on a gut fingerprint predicting immunoresistance to clinical routine use. Methods: NCT04567446 provided whole genome sequencing (WGS) of longitudinal fecal samples from patients (pts) with advanced non-small cell lung cancer (NSCLC) during ICI (alone or with chemotherapy) in France and Canada. Topological Pearson networks clustered into species interacting groups (SIG) correlating with overall survival (OS; OS&lt;12=NR; OS&gt;12=R). Forty harmful (SIG1) and thirty-four beneficial (SIG2) WGS species were associated with NR and R to ICI. A monodimensional score (TOPOSCORE) based on SIG1/SIG2 ratio combined with Akk relative abundance was calculated and compared to machine-learning (ML) algorithms. Multivariate Cox analysis (MVA) adjusted for established risk factors (ATB, gender, age, ECOG, PD-L1, LIPI score). Intraindividual dynamics of the TOPOSCORE was evaluated in pts with at least two fecal samples. Three independent cohorts of NSCLC and genitourinary (GU) cancers pts validated the data. Results: In n=245 and n=148 NSCLC pts, we could classify pts into dysbiotic (SIG1+,33%) and eubiotic (SIG2+, 67%), using the TOPOSCORE. Pts falling within the SIG2+ exhibited a significantly prolonged OS than pts falling into SIG1+ (HR: (95% CI), 0.50 (0.36-0.71), p&lt;0.0001). TOPOSCORE also predicted OS in 277 ICI-treated NSCLC and GU pts and compared to the state-of-the-art ML algorithms, held the highest percentage of correct predictions (63%). At MVA, TOPOSCORE was independently associated with OS (HR: 0.56 (0.39-0.81), p=0.002). Analyzing the intraindividual dynamics of the TOPOSCORE (n=67), we found that 74% of SIG2+ and 68% of SIG1+ individuals remained in their initial classification during ICI treatment. We finally scaled the calculation of the TOPOSCORE down to 24WGS (instead 75WGS) and set up a qPCR-based friendly-user test capable of accurately identifying the fecal presence of the bacteria of interest within 48 hrs. We confirmed (n=323) that OS was superior in those pts harboring a 24-bacteria-qPCR-based TOPOSCORE falling within the SIG2+ category (HR: 0.65 (0.48 to 0.87), p=0.0005). Conclusions: TOPOSCORE represents a robust biomarker predicting and following the dynamic of the immunoresistance to ICI across cancers on an individual basis. By converting the WGS TOPOSCORE to a qPCR-based test with a rapid turnaround time, it will be possible to adopt this score in routine clinical practice to improve pts stratification and ICI success rates guiding the selection of dysbiotic pts amenable to microbiota-centered interventions and eubiotic fecal microbiota transplantation donors. Clinical trial information: NCT04567446 .