Large Epidemiological Studies Research Articles

Prospective “common arm” comparison of US SWOG S0424 and Japanese JME studies in early-stage non-small cell lung cancer (NSCLC): Survival differences in the context of race, gender and smoking.

8036 Background: In NSCLC, overall frequencies and subtype distribution of EGFR and KRAS mutations differ significantly between Japanese and US patients. In many NSCLC clinical trials, Japanese patient outcomes appear superior to those in western populations. Since 2009, SWOG and Japanese investigators have used the “Common Arm” analytic method to interpret globally-conducted lung cancer clinical trials, providing a mechanism for direct patient-level comparisons in matching trials performed in the US and Japan. S0424 and the Japanese Molecular Epidemiology Study (JME) are large prospective molecular epidemiology studies conducted by SWOG and Japanese investigators and prospectively planned for “Common Arm” analysis. We investigated the effects of mutation distribution on overall survival in early stage NSCLC using data from JME and S0424. Methods: Both studies were designed to accrue representative proportions of ever-smokers (ES) versus never-smokers (NS) in male and female cohorts. Accrual to S0424 was completed in 2011 with 981 pts enrolled (Cheng et al JNCI 2018); JME was completed in 2012 with 957 pts (Kawaguchi et al JCO 2016). A comprehensive questionnaire was used to capture lifestyle, carcinogenic exposures, demographic and clinical data. Five years of follow-up was completed for each study. The association between baseline characteristics and mutation types were analyzed using multivariate logistic regression. The product-limit method was used to estimate overall survival and Cox regression models were fit to estimate hazard ratios. p-values were two-sided and p-values < 0.05 were considered significant. Results: Evaluable pts: 876 for JME; 957 for S0424. Demographic distribution: S0424: 87% Caucasian, 5% Asian, 4% Black; JME: 100% Japanese. As expected, multivariate logistic models adjusting for age, smoking status, gender and BMI showed JME were more likely to have EGFR mutations (p < 0.0001) and less likely to have KRAS mutations (p = 0.02). EGFR mutations were associated with never-smoking (p < 0.0001) and female sex (p < 0.0001); KRAS was associated with smoking (p < 0.0001). Adjusting for age, smoking status and gender, overall survival was greater in JME patients (p < 0.0001,HR = 0.49 (95% CI: 0.40-0.60)). In the subset of pts without an EGFR mutation, survival still favored the JME cohort (p < 0.001, HR = 0.68 (0.53-0.86). Conclusions: Patient level comparison of US (SWOG) and Japanese (JME) patients with early stage NSCLC demonstrated longer survival in Japanese patients even after adjusting for EGFR mutation frequency. Identification of factors that contribute to this finding are under investigation. Female sex remained a risk factor for EGFR mutation-driven disease in both populations. This analysis forms the basis for applying this population-related model in other clinical settings.

Validity of Measured vs. Self-Reported Weight and Height and Practical Considerations for Enhancing Reliability in Clinical and Epidemiological Studies: A Systematic Review.

Self-reported measures of height and weight are often used in large epidemiological studies. However, concerns remain regarding the validity and reliability of these self-reported measures. The aim of this systematic review was to summarise and evaluate the comparative validity of measured and self-reported weight and height data and to recommend strategies to improve the reliability of self-reported-data collection across studies. This systematic review adopted the PRISMA guidelines. Four online sources, including PubMed, Medline, Google Scholar, and CINAHL, were utilised. A total of 17,800 articles were screened, and 10 studies were eligible to be included in the SLR based on the defined inclusion and exclusion criteria. The findings from the studies revealed good agreement between measured and self-reported weight and height based on intra-class correlation coefficient and Bland-Altman plots. Overall, measured weight and height had higher validity and reliability (ICC > 0.9; LOA < 1 SD). However, due to biases such as social pressure and self-esteem issues, women underreported their weight, while men overreported their height. In essence, self-reported measures remain valuable indicators to supplement the restricted direct anthropometric data, particularly in large-scale surveys. However, it is essential to address potential sources of bias.

Quantification of 25-hydroxyvitamin D3 in dried blood spots as compared to plasma among Indian adults

Background Vitamin D may play an important role in later-life physical and cognitive health. Vitamin D status is standardly assessed in serum and plasma; however, collection, transport, and storage costs make large epidemiologic studies challenging. We assessed the agreement of 25-hydroxyvitamin D3 (25(OH)D3) quantification from dried blood spots (DBS) as compared to standard plasma assessment among older Indian adults. Methods A total of 58 adults over 45 years of age who resided in Pune, India were enrolled in the study from July 2020 to June 2021. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to assess 25(OH)D3 concentrations in paired plasma and DBS samples. Results Plasma and DBS 25(OH)D3 concentrations were highly correlated (Pearson’s correlation = 0.976). The median 25(OH)D3 concentration of the study population assessed by plasma was 14.6 ng/mL (Q1=12.0, Q3= 18.1) while the median concentration assessed in DBS was 12.8 ng/mL (Q1=11.0, Q3= 16.6). 25(OH)D3 concentrations measured from DBS were on average 6% (95% CI: 2-13%) lower than concentrations assessed by plasma across the observed 25(OH)D3 distribution. Conclusions We found good agreement between 25(OH)D3 quantification between DBS and plasma and our findings indicate that DBS can be used in epidemiologic studies of vitamin D among Indian adults.

Preconception depression reduces fertility: a couple-based prospective preconception cohort.

Is preconception depression associated with time to pregnancy (TTP) and infertility? Couples with preconception depression needed a longer time to become pregnant and exhibited an increased risk of infertility. Preconception depression in women contributes to impaired fertility in clinical populations. However, evidence from the general population-especially based on couples-is relatively scant. A couple-based prospective preconception cohort study was performed in 16 premarital examination centers between April 2019 and June 2021. The final analysis included 16521 couples who tried to conceive for ≤6 months at enrollment. Patients with infertility were defined as those with a TTP ≥12 months and those who conceived through ART. Couples' depression was assessed using the Patient Health Questionnaire-9 at baseline. Reproductive outcomes were obtained via telephone at 6 and 12 months after enrollment. Fertility odds ratios (FORs) and infertility risk ratios (RRs) in different preconception depression groups were analyzed using the Cox proportional-hazard models and logistic regression, respectively. Of the 16 521 couples analyzed, 10834 (65.6%) and 746 (4.5%) couples achieved pregnancy within the first 6 months and between the 6th and 12th months, respectively. The median (P25, P75) TTP was 3.0 (2.0, 6.0) months. The infertility rate was 13.01%. After adjusting for potential confounders, in the individual-specific analyses, we found that preconception depression in women was significantly related to reduced odds of fertility (FOR = 0.947, 95% CI: 0.908-0.988), and preconception depression in either men or women was associated with an increased risk of infertility (women: RR = 1.212, 95% CI: 1.076-1.366; men: RR = 1.214, 95% CI: 1.068-1.381); in the couple-based analyses, we found that-compared to couples where neither partner had depression-the couples where both partners had depression exhibited reduced fertility (adjusted FOR = 0.904, 95% CI: 0.838-0.975). The risk of infertility in the group where only the woman had depression and both partners had depression increased by 17.8% (RR = 1.178, 95% CI: 1.026-1.353) and 46.9% (RR = 1.469, 95% CI: 1.203-1.793), respectively. Reporting and recall bias were unavoidable in this large epidemiological study. Some residual confounding factors-such as the use of anti-depressants and other medications, sexual habits, and prior depressive and anxiety symptoms-remain unaddressed. We used a cut-off score of 5 to define depression, which is lower than prior studies. Finally, we assessed depression only at baseline, therefore we could not detect effects of temporal changes in depression on fertility. This couple-based study indicated that preconception depression in individuals and couples negatively impacts couples' fertility. Early detection and intervention of depression to improve fertility should focus on both sexes. This work was supported by grants from the National Natural Science Foundation of China (No. 82273638) and the National Key Research and Development Program of China (No. 2018YFC1004201). All authors declare no conflicts of interest. N/A.

Diabetes mellitus, metabolic syndrome, and sleep disorders: An underestimated relationship

Abstract Diabetes mellitus (DM) is the most prevalent endocrine disorder globally. DM is under-evaluated and less efficiently managed in terms of ruling out comorbid conditions associated with it and predisposing factors resulting in poor outcomes. Sleep disorders are more common than usually diagnosed due to less awareness in the community regarding the importance of timely diagnosis and the impact of interventions related to proper sleep hygiene and sleep structure. Obstructive sleep apnea (OSA) is independently associated with cardiovascular and cardiometabolic risk in several large epidemiological studies. OSA leads to several physiological disturbances, such as intermittent hypoxia, sleep fragmentation, and an increase in autonomic tone. Metabolic syndrome (MS) is an adverse outcome that is typically associated with obesity. It is a cluster of metabolic risk factors for type 2 DM (T2DM) and cardiovascular diseases (CVDs), including central obesity, hypertension, hyperglycemia, insulin resistance, and dyslipidemia. T2DM is often associated with OSA, and a bidirectional relationship may exist between the two diseases, mediated by both weight- and physiology-dependent mechanisms. OSA is highly associated with T2DM, and treatment of OSA may have a positive impact on the cardiometabolic profile. In this review, we have attempted to summarize the impact of sleep disorders on MS and DM, and vice versa, with special emphasis on newer medical options in the management of DM and cardiometabolic syndrome.

Young Trauma-Exposed Women with Low Sleep Effciency have Blunted Sympathetic Baroreflex Sensitivity and Higher Muscle Sympathetic Nerve Activity

Introduction: Poor sleep, a known risk factor for cardiovascular disease (CVD) and one of the American Heart Association’s essential 8th, is common after trauma-exposure. Although premenopausal women are thought to be protected from CVD, trauma exposure might increase their CVD risk. In a recent large epidemiological study examining sleep-related CVD comorbidities, the empirical cut off point for optimal sleep effciency (SE) was set at 83%, distinguishing between good and poor sleep effciency. Studies have suggested an overactive sympathetic nervous system and an impaired baroreflex sensitivity (BRS) as potential mechanisms of increased CVD risk. However, the impact of poor sleep effciency on muscle sympathetic nerve activity (MSNA) and BRS in young trauma-exposed women is unknown. We hypothesized that young trauma-exposed women with poor sleep effciency will present with impaired BRS and increased MSNA at rest. Methods: We collected data on 30 women (18 – 40 years) from diverse backgrounds who had been exposed to trauma. Sleep data was acquired via ActiWatch for 7 days and used to categorize our participants into two groups: good effciency (SE &gt; 83%, n=17) and poor effciency (SE &lt; 83%, n=13), with SE calculated as the percentage of time spent asleep while in bed. Additionally, we collected continuous noninvasive blood pressure (BP), heart rate (HR), and MSNA (burst frequency, incidence, and total activity) during 10 minutes of quiet rest. Sympathetic BRS was determined as the slope of the regression between individual sympathetic bursts and diastolic BP bins (3 mmHg), weighted against the number of cardiac cycles, utilizing an automated program (Ensemble, NZ). Results: There were no significant differences in trauma symptom severity, resting BP and HR between the two groups (p&gt;0.05 for all). However, resting sympathetic BRS was blunted in the poor SE (-0.10±0.88 bursts/100hb/mmHg) compared to the good SE (-1.44±1.58 bursts/100hb/mmHg, p=0.006) group, even after adjusting for age (p=0.009). Likewise, resting total MSNA was higher in the poor SE compared to the good SE after adjusting for age (p=0.028). MSNA burst frequency and burst incidence were comparable between the groups (p&gt;0.05). Conclusion: Our analyses revealed that poor sleep effciency is associated with decreased sympathetic baroreflex sensitivity and higher total muscle sympathetic activity at rest, regardless of age. Blunted sympathetic BRS may contribute to increased sympathetic activity in young women with poor sleep effciency. Future studies testing strategies to improve sleep effciency in this population could provide potential long-term cardiovascular benefits. UL1TR002494 and NIH K01HL161027 No disclosure. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Objective Sleep Effciency Is Negatively Associated with Resting Heart Rate in Young Trauma-Exposed Women with Poor Sleep

Introduction: Women are twice as likely as men to develop post-traumatic stress disorder (PTSD), a debilitating mental health disorder caused by a traumatic event that can lead to a higher risk of developing cardiovascular disease (CVD). Sleep is currently recognized as an essential component of cardiovascular health by the American Heart Association. Further, a large epidemiological study empirically set the cut-off point for normal sleep effciency (SE) at 83%, differentiating good sleep from poor sleep. Trauma-provoked sleep disturbances such as disruptive nocturnal behaviors and nightmares are a hallmark of PTSD. Yet, the impact of sleep disturbances on cardiovascular biomarkers such as blood pressure (BP) and heart rate (HR) in young trauma-exposed women is unknown. Therefore, the aim of our study was to investigate how objectively recorded sleep measures are associated with HR and BP in these young trauma-exposed women. We hypothesized that sleep quality will predict HR and/or BP, independently of the severity of trauma symptoms. Methods: We recruited 93 trauma-exposed young women (18-40 years). During the in-person visit, we measured BP and HR using an automated vital signs monitor. Additionally, we assessed trauma symptom severity using the PTSD checklist for DSM-5 (PCL5). After the laboratory visit, we sent participants home with a sleep watch (Philips Respironics) for 7 consecutive days, to quantify the percentage of time spent asleep while in bed. Given that a minimum of 83% SE is considered effcient sleep, we separated our data into two groups based on SE [good effciency (SE &gt;83%, n= 42) and poor effciency (SE &lt;83%, n= 51)]. Results: Participants’ mean age and body mass index were 26 ± 7 years and 25.7 ± 6.6 kg/m2 respectively. Pearson correlations revealed a negative correlation between resting HR and SE (r= -0.486, p&lt; 0.001) and HR and age (r= -0.246, p= 0.085) in the SE &lt;83% group. In contrast, there was no correlation between resting HR and SE (r= 0.025, p= 0.861) in the SE &gt;83% group. Therefore, we conducted further analysis in the SE &gt;83% group only. We observed a negative correlation between HR and the trauma symptoms subcluster of hyperarousal (r= -0.285, p= 0.045) in this poor SE group. Next, we ran a multiple linear regression predicting HR with SE, age, and the subclusters of hyperarousal and intrusion (affected by disruptive nocturnal behaviors and nightmares) as predictors. The model predicting HR was significant (R2= 0.366, p&lt; 0.001) and SE remained the strongest predictor (β= -0.458, p= 0.001) even when controlling for age, and trauma symptom subclusters, followed by age (β= -0.263, p= 0.037). Conclusion: Our analyses reveal that sleep effciency in trauma-exposed women is a strong predictor of resting HR, even when controlling for age and trauma symptoms subclusters of intrusion and hyperarousal. These findings suggest that in the context of trauma, it is the reduction in sleep effciency that has the greatest impact on resting heart rate, and ultimately mental health-associated CVD. K01HL161027 and UMN CTSI UL1TR002494 No Disclosure. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Radiation protection in a cohort of healthcare workers: knowledge, attitude, practices, feelings and IR-exposure in French hospitals

The number of healthcare workers occupationally exposed to ionizing radiation (IR) is increasing every year. As health effects from exposure to low doses IR have been reported, radiation protection (RP) in the context of occupational activities is a major concern. This study aims to assess the compliance of healthcare workers with RP policies, according to their registered cumulative dose, profession, and perception of radiation self-exposure and associated risk. Every healthcare worker from one of the participating hospitals in France with at least one dosimetric record for each year 2009, 2014, and 2019 in the SISERI registry was included and invited to complete an online questionnaire including information on the worker’s occupational exposure, perception of IR-exposure risk and RP general knowledge. Hp(10) doses were provided by the SISERI system. Multivariate logistic regressions were used. Dosimeter wearing and RP practices compliance were strongly associated with ‘feeling of being IR-exposed’ (OR = 3.69, CI95% 2.04–6.66; OR = 4.60, CI95% 2.28–9.30, respectively). However, none of these factors was associated with RP training courses attendance. The main reason given for non-compliance is unsuitability or insufficient numbers of RP devices. This study provided useful information for RP policies. Making exposed workers aware of their own IR-exposure seems to be a key element to address in RP training courses. This type of questionnaire should be introduced into larger epidemiological studies. Dosimeter wearing and RP practices compliance are associated to feeling being IR-exposed. RP training courses should reinforce workers’ awareness of their exposure to IR.

Age and Sex Differences in Pediatric Neuropathic Pain and Complex Regional Pain Syndrome: A Scoping Review.

Age and sex differences may exist in the frequency (incidence, prevalence) or symptoms of neuropathic pain (NP) and complex regional pain syndrome (CRPS) due to biopsychosocial factors (eg, neurodevelopment, physiological and hormonal changes, psychosocial differences) that evolve through childhood and adolescence. Age and sex differences may have implications for evaluating screening and diagnostic tools and treatment interventions. To map the existing literature on pediatric NP and CRPS with respect to age and sex distributions, and age and sex differences in symptomology and frequency. A scoping literature review was conducted. Databases were searched from inception to January 2023. Data were collected on study design, setting, demographics, and age and sex differences in frequency and symptoms. Eighty-seven studies were included. Distribution of participants with CRPS (n=37 studies) was predominantly early adolescence (10 to 14y) and female sex, while NP (n=42 studies) was most commonly reported throughout adolescence (10 to 19y) in both sexes. Forty-one studies examined age and sex differences in frequency; 6 studies reported higher frequency in adolescence. Very few studies (n=11) examined differences in symptomology. Large epidemiological studies are required to further understand age and sex differences in frequency of pediatric NP and CRPS. Age and sex differences must be considered when evaluating screening and diagnostic tools and treatment interventions to ensure relevance and validity to both sexes and across ages. Validated tools will improve understanding of age-dependent and sex-dependent differences in symptoms, pathophysiology, and psychosocial impact of pediatric NP and CRPS.

Incidence and Outcomes of Adult Syncope Presentations to Emergency Medical Services

Objective: The objectives of this systematic review were to evaluate the incidence, patient demographics and associated outcomes of adult syncope presentations to emergency medical services (EMS) within current literature.&#x0D; Methods: Inclusion criteria were contact with an EMS, a provisional diagnosis of syncope and epidemiological data regarding EMS contact with these patients. Exclusion criteria were all non-primary studies, patients given an alternative provisional diagnosis or who received life supporting interventions, studies that examined only presyncope presentations or were limited to paediatric patients, or that examined syncope within highly specific non-generalisable settings. Databases were searched on April 5th, 2022, and included Emcare, AMED, Medline, and CINAHL Plus. Quality assessment was conducted using the National Heart, Lung, and Blood Institute quality assessment tool. Data were manually extracted and collated with results synthesised using descriptive statistics and a narrative synthesis.&#x0D; Results: 12 studies were included in this review. Studies were primarily completed in Europe or the USA, and sample sizes ranged from 500 to 16 million. Most studies were rated as good to fair in quality. No studies specifically looked at the incidence or outcomes of syncope presentations to EMS. The reported incidence of syncope ranged between 0.09% and 24%.&#x0D; Discussion: Most studies were generalised epidemiological studies looking at EMS presentations. There were no studies that specifically looked at the incidence and outcomes of syncope presentations to EMS together. Instead, they were either large scale epidemiological studies that lack detailed analysis or had small samples focusing only on certain patient characteristics or presentations. An improved understanding of the epidemiological features of syncope presentations within the prehospital setting and their associated outcomes are of critical importance for the determination of risk stratification that can help guide clinical decision making by EMS.

The population-based Tromsø 8 study and e-mental health

IntroductionAgeing populations with increased needs, rising costs of traditional services, and new technologies are some factors driving the use of e-health services. A Norwegian study with data from 2015-2016 found that 13.5% had used apps, 7.3% had used social media, and 5% had used video services for health purposes. Little is known about the effects of many online health services, but in general they seem to increase knowledge and make most people feel reassured, although some users feel more anxious or confused after using such tools. Recent technological developments have resulted in new online health services, including AI-based technologies. More updated knowledge regarding the population’s use of e-health services in general and e-mental health services in particular, is needed.ObjectivesThe objective here is to provide information about an upcoming large population-based epidemiological study and how it addresses e-health and e-mental health.MethodsWe introduce the upcoming 8th version of the epidemiological Tromsø Study and discuss its importance to the field of e-mental health.Results The Tromsø epidemiological study has since 1974 taken place in the Norwegian municipality of Tromsø. It contains information on a range of topics within health and illness, including topics from many medical specialities, psychiatry and substance use. In the upcoming 8th version of the study (2025-2026), more than 33,000 people aged above 40 will be invited to participate. The main questionnaire will include questions relating to a wide variety of topics, including on e-health use. We suspect the importance of e-health and e-mental health have increased lately, and we will examine how the use of e-health may impact mental health.ConclusionsCommunity-based studies, such as the Tromsø Study, allow researchers to study associations between many different variables, including mental health and e-health. The upcoming Tromsø 8 study will enable us to study e-health use and its relationship to mental health in a large sample representative of the Norwegian population.Disclosure of InterestNone Declared

Traumatic rhabdomyolysis: rare but morbid, potentially lethal, and inconsistently monitored

PurposeAlthough traumatic rhabdomyolysis (TR) is shown to be associated with acute kidney injury (AKI), there are no large prospective epidemiological studies, interventional trials, official guidelines outlining the appropriate investigation, monitoring, and treatment on this poorly understood condition. We aimed to establish the contemporary epidemiology and describe current practices for TR to power future higher quality studies. We hypothesised that investigation and monitoring occur in an ad hoc fashion.Material and methodsWe conducted a 1-year retrospective cohort study of all patients > 16 years of age, with an ISS > 12 and, admitted to a level 1 trauma centre. Demographics, initial vital signs, admission laboratory values, and daily creatinine kinase (CK) values were collected. The primary outcome was TR (defined by CK > 5000 IU), secondary outcomes included AKI (KDIGO criteria), mortality, multiple organ failure, length of stay, and need for renal replacement therapy (RRT).Results586 patients met inclusion criteria and 15 patients (2.56%) developed TR. CK testing occurred in 78 (13.1%) patients with 29 (37.7%) of these having values followed until downtrending. AKI occurred in 63 (10.8%) patients within the entire study population. Among those with TR, nine (60%) patients developed AKI. Patients with TR had higher ISS (median 29 vs 18) and mortality (26.7% vs 8.9%).DiscussionWhilst TR appears rare without liberal screening, it is strongly associated with AKI. Given the poor outcomes, standardised monitoring, and liberal testing of CK could be justified in trauma patients with higher injury severity. This epidemiological data can help to define study populations and power future multicentre prospective studies on this infrequent yet morbid condition.

Abstract 3562: Comparison of spatial co-localization measures for studying the tumor immune microenvironment with application to ovarian cancer

Abstract Introduction: The spatial contexture of the tumor immune microenvironment (TIME) has been associated with survival among cancer patients, including women with high-grade serous ovarian cancer (HGSOC). However, an assessment of statistical approaches to quantify the spatial characteristics of the TIME has not been conducted. Moreover, it is unknown which statistical approach is most sensitive in identifying spatial co-localization of two cell types in the TIME. Methods: Using the R package scSpatialSIM that simulates spatial single-cell protein data (i.e., multiplex immunofluorescence data), we completed a simulation study to compare four methods for assessing co-localization of cell types in the TIME (Ripley’s K, Nearest Neighbor G, Dixon’s segregation statistic, and a spatial interaction variable). The simulation study varied the cell abundance (e.g., low vs high), the co-localization (e.g., co-localization, random, segregation), and the variation in the marked point process. In addition to the simulated data, we assessed the four methods in large epidemiological studies (Nurses’ Health Study [NHSI/NHSII], New England Case Control Study [NECC], African American Cancer Epidemiology Study [AACES], and North Carolina Ovarian Cancer Study [NCOCS]) including 756 women with HGSOC. Multiplex immunofluorescence was conducted using AKOYA Biosciences OPALTM platform to measure cytotoxic T cells (CTLS) and regulatory T cells (Tregs). Cox proportional hazards regression models were fit to estimate the association of spatial co-localization of CTLS and Tregs with overall survival. Results: In the simulation study, we found that Ripley’s K was the most powerful approach for assessing co-localization for a variety of simulation scenarios. Surprisingly, the other approaches (Nearest Neighbor G, Dixon’s Segregation statistic, and spatial interaction statistic) were unable to detect the simulated co-localization of two cell types in most simulation scenarios. In the analysis of women with HGSOC in the epidemiological cohorts, we were able to detect significant co-localization of CTLS and Tregs in 40.2%, 12.2%, 21.2%, and 17.0% of samples using Ripley’s K, Nearest Neighbor G, Dixon’s statistic, and the interaction variable methods, respectively. However, the level of co-localization was not associated with survival. Conclusions: We found that Ripley’s K was the most powerful at detecting simulated co-localization of two cell types in the TIME. Similarly, Ripley’s K identified the highest level of significant spatial co-localization of CTLS and Tregs in the application to HGSOC. However, we did not observe an association of co-localization of CTLS and Tregs with overall survival. Future work is needed to develop powerful approaches for quantifying the spatial contexture of the TIME, along with assessment of the statistical properties of these methods. Citation Format: Brooke L. Fridley, Alex Soupir, Julia Wrobel, Christelle Colin-Leitzinger, Mary K. Townsend, Andrew B. Lawson, Kathryn L. Terry, Joellen M. Schildkraut, Shelley S. Tworoger, Lauren C. Peres. Comparison of spatial co-localization measures for studying the tumor immune microenvironment with application to ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3562.

Vaccination in Prevention of Acute Cardiovascular Events in Adults

Epidemiological studies have shown that acute coronary events, heart failure, atrial fibrillation with fast ventricular rate and brain stroke events have increased prevalence in winter season. Infections have a pivotal role in triggering such events. Vaccination against influenza and pneumococcus has been documented to prevent such events in large epidemiological studies. Majority of the deaths during Corona virus-19 (COVID-19) pandemic were related to cardiovascular event apart from serious lung condition. Vaccination has been proven to reduce risk of recurrent hospitalizations and death especially in sick and frail patients with heart failure, chronic obstructive lung diseases, renal failure and acute coronary syndromes. It becomes more relevant in countries like India where patient has to pay huge amounts for hospitalization from the pocket. On the other hand, it reduces unnecessary strain on the healthcare manpower and resources. Practice of vaccination in addition to guidelines based pharmacological, device or surgical therapy, is to help both the patients and physicians.

A model for stimulation of enzyme activity by a competitive inhibitor based on the interaction of terazosin and phosphoglycerate kinase 1

The drug terazosin (TZ) binds to and can enhance the activity of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1) and can increase ATP levels. That finding prompted studies of TZ in Parkinson's disease (PD) in which decreased neuronal energy metabolism is a hallmark feature. TZ was neuroprotective in cell-based and animal PD models and in large epidemiological studies of humans. However, how TZ might increase PGK1 activity has remained a perplexing question because structural data revealed that the site of TZ binding to PGK1 overlaps with the site of substrate binding, predicting that TZ would competitively inhibit activity. Functional data also indicate that TZ is a competitive inhibitor. To explore the paradoxical observation of a competitive inhibitor increasing enzyme activity under some conditions, we developed a mass action model of TZ and PGK1 interactions using published data on PGK1 kinetics and the effect of varying TZ concentrations. The model indicated that TZ-binding introduces a bypass pathway that accelerates product release. At low concentrations, TZ binding circumvents slow product release and increases the rate of enzymatic phosphotransfer. However, at high concentrations, TZ inhibits PGK1 activity. The model explains stimulation of enzyme activity by a competitive inhibitor and the biphasic dose-response relationship for TZ and PGK1 activity. By providing a plausible mechanism for interactions between TZ and PGK1, these findings may aid development of TZ or other agents as potential therapeutics for neurodegenerative diseases. The results may also have implications for agents that interact with the active site of other enzymes.

Unraveling the Link between Ιnsulin Resistance and Bronchial Asthma.

Evidence from large epidemiological studies has shown that obesity may predispose to increased Th2 inflammation and increase the odds of developing asthma. On the other hand, there is growing evidence suggesting that metabolic dysregulation that occurs with obesity, and more specifically hyperglycemia and insulin resistance, may modify immune cell function and in some degree systemic inflammation. Insulin resistance seldom occurs on its own, and in most cases constitutes a clinical component of metabolic syndrome, along with central obesity and dyslipidemia. Despite that, in some cases, hyperinsulinemia associated with insulin resistance has proven to be a stronger risk factor than body mass in developing asthma. This finding has been supported by recent experimental studies showing that insulin resistance may contribute to airway remodeling, promotion of airway smooth muscle (ASM) contractility and proliferation, increase of airway hyper-responsiveness and release of pro-inflammatory mediators from adipose tissue. All these effects indicate the potential impact of hyperinsulinemia on airway structure and function, suggesting the presence of a specific asthma phenotype with insulin resistance. Epidemiologic studies have found that individuals with severe and uncontrolled asthma have a higher prevalence of glycemic dysfunction, whereas longitudinal studies have linked glycemic dysfunction to an increased risk of asthma exacerbations. Since the components of metabolic syndrome interact with one another so much, it is challenging to identify each one's specific role in asthma. This is why, over the last decade, additional studies have been conducted to determine whether treatment of type 2 diabetes mellitus affects comorbid asthma as shown by the incidence of asthma, asthma control and asthma-related exacerbations. The purpose of this review is to present the mechanism of action, and existing preclinical and clinical data, regarding the effect of insulin resistance in asthma.

Abstract IA18: Genetic susceptibility to breast cancer: Recent advances and application to personalised prevention

Abstract The past two decades have seen dramatic progress in our understanding of the inherited basis of breast cancer, driven by large international collaborative epidemiological studies. Genetic factors identified include rare coding variants in susceptibility genes, and more than 200 common polymorphisms, identified through genome-wide association studies (GWAS) and largely in non-coding regions, that confer more moderate risks. The majority of the common variants are more strongly associated with ER-positive disease, but a subset is specifically associated with ER-negative disease. Variants are strongly enriched for regulatory regions and transcription factor binding sites, and the putative target genes are strongly enriched for known breast cancer drivers: however, the underlying target genes and mechanisms remain largely obscure. The associations for common variants appear to be largely independent of each other and can be summarised by a polygenic risk score (PRS) that is strongly predictive of risk. The most extensively validated PRS, comprising 313 SNPs, is associated with a relative risk of approximately 1.6 per standard deviation; women in the top 1% of the risk distribution have an approximately 4-fold risk of ER-positive disease and 3-fold risk of ER-negative disease. The PRS was developed in women of European ancestry but is also predictive of risk in Asian ancestry women, though less so in African ancestry women. In contrast, despite their widespread use, the evidence for association with cancer for coding variants in genes on genetic testing panels is often weak. Recent very large-scale targeted sequencing studies, however, have clarified the position, providing strong evidence for an association between protein truncating or missense variants and breast cancer risk for nine genes: BRCA1, BRCA2, ATM, CHEK2, PALB2, BARD1, RAD51C, RAD51D and TP53. Recent large-scale exome-wide sequencing analysis has shown that rare variants in several additional genes are also risk associated, with the majority being tumour suppressor genes: these include MAP3K1, ATRIP and SAMHD1. These analyses also demonstrate, however, that the contribution of coding variation, beyond the known genes, is likely to be small. The currently identified variants explain about half of the familial risk of breast cancer. Part of the “missing” heritability is due to weaker common variants, many of which should be identified in ongoing larger GWAS. The causes of the remainder are obscure and may include rare non-coding variants, repeat polymorphisms, and epistatic interactions. Risk discrimination is most powerful when all risk factors are considered. The BOADICEA model, implemented in the CanRisk tool, provides a well validated model that incorporates the effects of gene variants, polygenic risk scores, lifestyle factors and breast density to predict breast and ovarian cancer risk. Multiple translational studies are ongoing to evaluate the feasibility and utility of such personalised risk prediction for stratifying screening and prevention. Citation Format: Douglas F Easton. Genetic susceptibility to breast cancer: Recent advances and application to personalised prevention [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr IA18.

The Association Between Ultra-Processed Food Consumption and Chronic Insomnia in the NutriNet-Santé Study

BackgroundThe consumption of ultra-processed foods (UPF) is on the rise worldwide, and it has been linked to numerous health conditions, such as diabetes, obesity, and cancer. Few studies have focused on the effect of UPF consumption on sleep health and even fewer on chronic insomnia. ObjectiveThis study investigated the association between UPF intake and chronic insomnia in a large population-based sample. DesignThis was a cross-sectional analysis using the NutriNet-Santé study data, an ongoing Web cohort in France. Participants/settingThirty-eight thousand five hundred seventy adult males and females who had completed a sleep questionnaire (2014) and at least two 24-hour dietary records were included in the analysis. Main outcomes measuresChronic insomnia was defined according to established criteria. Categorization of food and beverages as UPF was based on the NOVA–Group 4 classification. Statistical analyses performedThe cross-sectional association between UPF intake and chronic insomnia was assessed using multivariable logistic regression. ResultsAmong the 38,570 participants (mean age, 50.0 ±14.8 years, 77.0% female) included in the analysis, 19.4% had symptoms of chronic insomnia. On average, UPF represented 16% of the total amount (g/day) of the overall dietary intake. In the fully adjusted model, UPF consumption was associated with higher odds of chronic insomnia (odds ratio [OR] for an absolute 10% greater UPF intake in the diet = 1.06; 95% confidence interval [CI]: 1.02–1.09). Sex-specific OR for chronic insomnia for an absolute 10% greater UPF intake in the diet were 1.09 (1.01–1.18) among males and 1.05 (1.01–1.09) among females. ConclusionsThis large epidemiological study revealed a statistically significant association between UPF intake and chronic insomnia, independent of sociodemographic, lifestyle, diet quality, and mental health status covariates. The findings provide insights for future longitudinal research as well as nutrition- and sleep-focused intervention and prevention programs.

Distribution of the C9orf72 hexanucleotide repeat expansion in healthy subjects: a multicenter study promoted by the Italian IRCCS network of neuroscience and neurorehabilitation.

High repeat expansion (HRE) alleles in C9orf72 have been linked to both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD); ranges for intermediate allelic expansions have not been defined yet, and clinical interpretation of molecular data lacks a defined genotype-phenotype association. In this study, we provide results from a large multicenter epidemiological study reporting the distribution of C9orf72 repeats in healthy elderly from the Italian population. A total of 967 samples were collected from neurologically evaluated healthy individuals over 70 years of age in the 13 institutes participating in the RIN (IRCCS Network of Neuroscience and Neurorehabilitation) based in Italy. All samples were genotyped using the AmplideXPCR/CE C9orf72 Kit (Asuragen, Inc.), using standardized protocols that have been validated through blind proficiency testing. All samples carried hexanucleotide G4C2 expansion alleles in the normal range. All samples were characterized by alleles with less than 25 repeats. In particular, 93.7% of samples showed a number of repeats ≤10, 99.9% ≤20 repeats, and 100% ≤25 repeats. This study describes the distribution of hexanucleotide G4C2 expansion alleles in an Italian healthy population, providing a definition of alleles associated with the neurological healthy phenotype. Moreover, this study provides an effective model of federation between institutes, highlighting the importance of sharing genomic data and standardizing analysis techniques, promoting translational research. Data derived from the study may improve genetic counseling and future studies on ALS/FTD.

P459 The prevalence and characteristics of inflammatory bowel disease-related ocular involvement in children

Abstract Background Ocular manifestations (OM) in patients with inflammatory bowel disease (IBD) are uncommon, particularly in children. We aimed to explore the prevalence, characteristics and risk factors of IBD associated OM in a large epidemiologic cohort-based study. Methods A cross-sectional study was performed using the Maccabi Healthcare Services (MHS) database. The eligible population included all patients diagnosed with IBD as children (&amp;lt;18 years) between January 2005 and July 2023. An additional analysis was conducted on patients diagnosed with ocular disease during childhood (&amp;lt;18 years) and IBD during childhood or adulthood. Results Out of 2,567 children with IBD (males 55%, Crohn’s disease 64%), 78 (3%) were diagnosed with OM at any time during disease course. In 54 patients (69%), the OM occurred after IBD diagnosis with a median time of 2.6 (0.47-7) years between the two events, whereas in 24 patients (31%) OM preceded IBD diagnosis with a median time of 2.1 (0.6-5.7) years. OM was significantly associated with Crohn’s disease, compared with ulcerative colitis (78.2% vs. 63.6% in the entire cohort; p=0.03). The presence of OM was associated with increased usage of systemic corticosteroids (p&amp;lt;0.001), biologic agents (p=0.04) and longer duration since IBD diagnosis (p=0.04). There were 55 patients with OM during childhood who were ever diagnosed with IBD. In this population OM was also associated with increased usage of systemic corticosteroids (p&amp;lt;0.001) and increased hospitalization rate per year (p=0.048). The annual prevalence of OM increased gradually from 10/1000 patients in 2005 to 22/1000 patients in 2022 (p=0.55). Conclusion Ocular involvement in children with IBD is rare and more common in patients with Crohn’s disease with a stable prevalence rate. It is associated with a longer duration of disease, greater usage of systemic corticosteroids and biologic agents and with a higher rate of hospitalizations, potentially representing a more severe disease course.