Case-control Analysis Research Articles

Risk factors for infection with influenza A(H3N2) virus on a US university campus, October-November 2021.

Knowledge of the specific dynamics of influenza introduction and spread in university settings is limited. Persons with acute respiratory illness symptoms received influenza testing by molecular assay during October 6-November 23, 2022. Viral sequencing and phylogenetic analysis were conducted on nasal swab samples from case-patients. Case-control analysis of a voluntary survey of persons tested was used to identify factors associated with influenza; logistic regression was conducted to calculate odds ratios and 95% CIs. A subset of case-patients tested during the first month of the outbreak was interviewed to identify sources of introduction and early spread. Among 3268 persons tested, 788 (24.1%) tested positive for influenza; 744 (22.8%) were included in the survey analysis. All 380 sequenced specimens were influenza A (H3N2) virus clade 3C.2a1b.2a.2, suggesting rapid transmission. Influenza (OR [95% CI]) was associated with indoor congregate dining (1.43 [1.002-2.03]), attending large gatherings indoors (1.83 [1.26-2.66]) or outdoors (2.33 [1.64-3.31]), and varied by residence type (apartment with ≥1 roommate: 2.93 [1.21-7.11], residence hall room alone: 4.18 [1.31-13.31], or with roommate: 6.09 [2.46-15.06], or fraternity/sorority house: 15.13 [4.30-53.21], all compared with single-dwelling apartment). Odds of influenza were lower among persons who left campus for ≥1day during the week before their influenza test (0.49 [0.32-0.75]). Almost all early cases reported attending large events. Congregate living and activity settings on university campuses can lead to rapid spread of influenza following introduction. Isolating following a positive influenza test or administering antiviral medications to exposed persons may help mitigate outbreaks.

Risk of Diarrhea in Infants on Breastfeeding Exclusive and Non-Exclusive Breastfeeding

Diarrheal disease is a significant risk factor for morbidity and mortality worldwide in children under five years of age. The study aimed to analyze the risk factors for diarrhea in infants with and without exclusive breastfeeding. The research approach used a case-control analysis with observational analytic methods. The population was all mothers who gave birth to babies aged 6-12 months. By determining the sample using the Lemeshow formula, the example was 152 babies with details of 76 cases and 76 controls. The results of the chi-square test showed (p-value= 0,000), which means that there was an effect of exclusive breastfeeding and non-exclusive breastfeeding with the incidence of diarrhea in infants with a value of OR=12,065, which means that mothers who did not breastfeed their babies 12,065 times more at risk of suffering from diarrhea higher inversely compared to mothers who exclusively breastfeed their babies. In conclusion, infants who are not exclusively breastfed are at risk of suffering from diarrhea than infants who are exclusively breastfed.

Effectiveness of Monovalent mRNA COVID-19 Vaccination in Preventing COVID-19–Associated Invasive Mechanical Ventilation and Death Among Immunocompetent Adults During the Omicron Variant Period — IVY Network, 19 U.S. States, February 1, 2022–January 31, 2023

As of April 2023, the COVID-19 pandemic has resulted in 1.1 million deaths in the United States, with approximately 75% of deaths occurring among adults aged ≥65 years (1). Data on the durability of protection provided by monovalent mRNA COVID-19 vaccination against critical outcomes of COVID-19 are limited beyond the Omicron BA.1 lineage period (December 26, 2021-March 26, 2022). In this case-control analysis, the effectiveness of 2-4 monovalent mRNA COVID-19 vaccine doses was evaluated against COVID-19-associated invasive mechanical ventilation (IMV) and in-hospital death among immunocompetent adults aged ≥18 years during February 1, 2022-January 31, 2023. Vaccine effectiveness (VE) against IMV and in-hospital death was 62% among adults aged ≥18 years and 69% among those aged ≥65 years. When stratified by time since last dose, VE was 76% at 7-179 days, 54% at 180-364 days, and 56% at ≥365 days. Monovalent mRNA COVID-19 vaccination provided substantial, durable protection against IMV and in-hospital death among adults during the Omicron variant period. All adults should remain up to date with recommended COVID-19 vaccination to prevent critical COVID-19-associated outcomes.

Metabolic factors associated with incident fracture among older adults with type 2 diabetes mellitus: a nested case-control study.

Type 2 diabetes mellitus (T2D) is associated with an increased risk of fracture despite a paradoxically higher bone mineral density. Additional markers of fracture risk are needed to identify at-risk individuals. The MURDOCK study is an ongoing study, initiated in 2007, of residents in central North Carolina. At enrollment, participants completed health questionnaires and provided biospecimen samples. In this nested case-control analysis, incident fractures among adults with T2D, age ≥ 50years, were identified by self-report and electronic medical record query. Fracture cases were matched 1:2 by age, gender, race/ethnicity, and BMI to those without incident fracture. Stored sera were analyzed for conventional metabolites and targeted metabolomics (amino acids and acylcarnitines). The association between incident fracture and metabolic profile was assessed using conditional logistic regression, controlled for multiple confounders including tobacco and alcohol use, medical comorbidities, and medications. 107 incident fractures were identified with 210 matched controls. Targeted metabolomics analysis included 2 amino acid factors, consisting of: 1) the branched chain amino acids, phenylalanine and tyrosine; and 2) glutamine/glutamate, asparagine/aspartate, arginine, and serine [E/QD/NRS]. After controlling for multiple risk factors, E/QD/NRS was significantly associated with incident fracture (OR 2.50, 95% CI: 1.36-4.63). Non-esterified fatty acids were associated with lower odds of fracture (OR 0.17, 95% CI: 0.03-0.87). There were no associations with fracture among other conventional metabolites, acylcarnitine factors, nor the other amino acid factors. Our results indicate novel biomarkers, and suggest potential mechanisms, of fracture risk among older adults with T2D.

Immunocompromise and herpes simplex virus type 1 encephalitis (HSVE): a nationwide cohort and case-control study (S25.009)

<h3>Objective:</h3> We aim to determine whether a relationship exists between immunocompromise as defined by autoimmune disease or immunosuppressive and immunomodulatory medications in patients and incident HSVE. <h3>Background:</h3> Among infectious etiologies of encephalitis, herpes simplex virus type 1 (HSV-1) is commonest. The association between immune status and HSVE is unclear. Using a U.S. Medicaid database of 75.6 million persons, we evaluated the association between HSVE and autoimmune conditions, exposure to immunosuppressive and immunomodulatory medications, and other medical comorbidities. <h3>Design/Methods:</h3> We used the U.S. Medicaid Analytic eXtract Database between the years of 2007–2010 from the 29 most populated American states. We first examined the crude incidence of HSVE in the population. We then age- and sex-matched adult cases of HSVE with a sufficient enrolment period to a larger control population without HSVE. In a case-control analysis, we examined the association between HSVE and exposure to both autoimmune disease and immunosuppressive/immunomodulatory medications. Analyses were conducted with conditional logistic regression progressively adjusting for sociodemographic factors, Charlson comorbidity index, and non-autoimmune comorbidities. <h3>Results:</h3> Incidence of HSVE was ~3.01 per 10⁵ person-years among adults. A total of 951 HSVE cases and 95,100 age- and sex-matched controls were compared. The HSVE population had higher rates of medical comorbidities than the control population. The association of HSVE and autoimmune conditions was strong, adjusted OR 2.6 (95% CI [2.2, 3.2]). The association of HSVE and immunomodulating medications had an OR of 2.2 [1.9, 2.6], also after covariate adjustment. When both exposures were included in regression models, the associations remained robust: 2.3 [1.9, 2.7] for autoimmune disease and 2.0 [1.7, 2.3] for immunosuppressive and immunomodulatory medications. <h3>Conclusions:</h3> In a large, national population, HSVE is strongly associated with pre-existing autoimmune disease and exposure to immunosuppressive and immunomodulatory medications. The role of antecedent immune-related dysregulation may have been underestimated to date. <b>Disclosure:</b> Dr. Tang has received personal compensation for serving as an employee of Third Rock Ventures. Dr. Bhattacharyya has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion Pharmaceuticals. Dr. Bhattacharyya has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Continuum. The institution of Dr. Bhattacharyya has received research support from Alexion Pharmaceuticals. The institution of Dr. Bhattacharyya has received research support from National Institute of Health. The institution of Dr. Bhattacharyya has received research support from UCB. Dr. Bhattacharyya has received publishing royalties from a publication relating to health care. Dr. Bhattacharyya has received publishing royalties from a publication relating to health care. Dr. Bhattacharyya has received publishing royalties from a publication relating to health care. Dr. Miyawaki has received personal compensation in the range of $50,000-$99,999 for serving as an officer or member of the Board of Directors for Family Health, Inc.. Dr. Miyawaki has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Morrison and Mahoney. Dr. Miyawaki has stock in Cincinnati Bengals. Dr. Miyawaki has received publishing royalties from a publication relating to health care. Dr. Miyawaki has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant with US Department of Health and Human Services. Dr. Yoshida has received personal compensation for serving as an employee of OM1, Inc. Dr. Yoshida has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for OM1, Inc. Dr. Wilcox has nothing to disclose. Karen Costenbader has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amgen. Karen Costenbader has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Lilly. Karen Costenbader has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Glaxo Smith Kline. Karen Costenbader has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for AstraZeneca Pharmaceuticals LP. Karen Costenbader has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Arthritis and Rheumatology. Karen Costenbader has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Uptodate. Karen Costenbader has stock in Neutrolis. The institution of Karen Costenbader has received research support from Gilead. The institution of Karen Costenbader has received research support from Exagen. The institution of Karen Costenbader has received research support from Merck. Karen Costenbader has received personal compensation in the range of $0-$499 for serving as a grant reviewer with NIH. Prof. Solomon has nothing to disclose. Mr. Guan has nothing to disclose. Miss Lahey has nothing to disclose.

Opium as a risk factor for early-onset coronary artery disease: Results from the Milano-Iran (MIran) study.

The spreading of opium use poses new health related concerns. In some areas of Asia its use is believed to protect from cardiovascular disorders, such as coronary artery disease (CAD). However, whether opium use has an association with CAD is unclear. We aimed to investigate the association between non-medical opium use and CAD. We set up a case-control analysis, i.e., the Milano-Iran (MIran) study by enrolling consecutive young patients who underwent a coronary angiography at the Tehran Heart Center, between 2004 and 2011. Incident cases with CAD were contrasted with controls for opium use. Relative risks were calculated in terms of odds ratios (ORs) by logistic regression models adjusted for age, sex, cigarette smoking, body mass index, hypertension, hyperlipidaemia, and diabetes. Interaction analyses were performed between opium and major cardiovascular risk factors. 1011 patients with CAD (mean age 43.6 years) and 2002 controls (mean age 54.3 years) were included in the study. Habitual opium users had a 3.8-fold increased risk of CAD (95%CI 2.4-6.2) compared with non-users. The association was strongest for men, with a fully adjusted OR of 5.5 (95%CI 3.0-9.9). No interaction was observed for the combination of opium addiction and hypertension, or diabetes, but an excess in risk was found in opium users with hyperlipidaemia (OR 16.8, 95%CI 8.9-31.7, expected OR 12.2), suggesting supra-additive interaction. In conclusion, despite common beliefs, we showed that non-medical opium use is associated with an increased risk of CAD, even when other cardiovascular risk factors are taken into account.

Incidence and risk factors for postpartum hemorrhage after vaginal delivery: A systematic review and meta-analysis.

To estimate the incidence and identify risk factors of postpartum hemorrhage (PPH) after vaginal delivery. A systematic review and meta-analysis was conducted. PubMed, Cochrane Library, CINAHL, Web of Science, EMBASE, and ClinicalTrials.gov databases were systematically searched from inception to April 30th, 2022. Cross-sectional, cohort, case-control, and secondary analysis of randomized controlled studies that reported the incidence of PPH and the related risk factors in vaginal delivery were eligible through screening of 2343 articles. The incidence, associated standard error, adjusted odds ratios, relative risks and associated 95% confidence intervals were combined in the meta-analysis. Thirty-six articles were included in the descriptive review. The incidence of PPH (blood loss ≥500 mL and blood loss ≥1000 mL) was 17% and 6%, respectively. Forty-one identified risk factors were divided into five categories under two criteria: history and demographics; maternal comorbidity; pregnancy-related factors; labor-related factors; delivery-related factors. With the increasing incidence of PPH globally, obstetric health care providers need to improve their awareness of these multi-factorial risks to optimize obstetric care and reduce maternal morbidity. This systematic review and meta-analysis have raised important questions about the nature of vaginal delivery, such as the duration of prolonged labor, details on the use of oxytocin, and the presence of genital tract trauma. There should be highlighted by obstetric personnel on these factors during a patients' labor process.

The Effects of Blue-Light Filtering Intraocular Implants on Glare Geometry

Purpose One common complaint with natural opacified lenses is the deleterious effects of higher-order ocular aberrations and intraocular scatter, such as halos and starbursts, which are not always remedied with surgery and intraocular lens (IOL) implantation. Blue-light filtering (BLF) IOL filter scatter-prone short-wave light. Here, we determine whether BLF IOL reduce halo and starburst size. Methods This study was a case-control design, between- and within-subjects (contralateral implantation). Sixty-nine participants with either the BLF IOL (n = 25; AlconSN60AT), clear IOL (n = 24; AlconSA60AT or WF), or both (n = 20) IOL participated. Participants were exposed to a point source of broadband simulated sunlight, which created the appearance of halos/starbursts. Dysphotopsia was measured as the diameter of broadband light-induced halos and starbursts. Results A case-control analysis. Halo size was significantly larger (t[35.05] = 2.98, p = 0.005) in participants with the clear control lens (M = 3°55′ ± 2°48′), compared to the BLF IOL (M = 1°84′ ± 1°34′). Starburst size was not significantly different between groups. Contralateral analysis. Halo size was significantly smaller (t = −3.89, p = .001) in test eyes with the BLF (M = 3°16′ ± 2°35′) compared to the fellow control eyes (M = 5°42′ ± 3°17′). Starburst size was also significantly smaller (t = −2.60, p < 0.018) in BLF test eyes (M = 9°57′ ± 4°25′) than the fellow eye with the clear IOL (M = 12°33′ ± 5°25′). Conclusions BLF IOL filter short-wave light and mimic retinal screening by the young, natural crystalline lens. Such filtering can reduce some deleterious effects of bright light by decreasing ocular diffusion/halos and starbursts.

Obesity is Not Associated with Adverse Perioperative or Poorer Clinical Outcomes following Thoracic and Fenestrated-Branched Endovascular Aortic Repair

Obesity is a risk factor for higher morbidity and mortality following open aortic repair but currently there is limited literature on its impact on clinical and procedural outcomes following thoracic endovascular aortic repair (TEVAR) and branched-fenestrated endovascular aortic repair (B-FEVAR). We conducted a retrospective case-control analysis of a prospectively collected nonrandomized database to evaluate the effects of obesity on procedural and clinical outcomes after B-FEVAR/TEVAR in treatment of pararenal/thoracoabdominal aortic aneurysm and dissection at the University hospital of Nantes (France) between January 2016 and December 2021. Patients were divided in 2 groups according to their body mass index (BMI) and the rate of technical success, complications (renal, pulmonary, cardiac, and neurological events), 30-day and long-term survival, freedom from target vessel instability and reintervention were compared. 195 patients were included (mean age 69.6 DS±11.2; n=135, 69.2% men; mean BMI: 26.6kg/m2 range 19-41) totalling n=72 (36.8%) TEVAR, n=107 (55.4%) FEVAR and n=14 (7.3%) BEVAR. Patients were divided in 2 groups [obese: BMI≥30kg/m2n=52 (26.7%); and nonobese, BMI<30kg/m2, n=143 (73.3%) that statistically differed only in terms of coronary artery disease (obese 42.3% vs. 26.6% nonobese, P=0.035) and diabetes (obese 25% vs. 12.6% nonobese, P=0.03). No statistical differences were noted in primary technical (94.2% vs. 94.4%, P=1.00) and clinical (92.3% vs. 95.1%, P=0.49) success. Overall morbidity (30.8% vs. 21.1%, P=0.16), visceral vessels instability (1.9% vs. 1.4% P=1.00), reintervention rate within 30days (9.6% vs. 5.6% P=0.33), 90days (7.7% vs. 9.8%, P=0.78) and during follow-up (9.8% vs. 20%, P=0.14) were comparable. No statistical difference were noted in 30-day mortality (3.8% vs. 4.9%, P=1.00) and the 2-year follow-up survival (86.8% vs. 78.4%, P=0.180) between the 2 groups. In this series, obesity was not associated to worst clinical outcomes or higher mortality rate following TEVAR/B-FEVAR. However, considering our small patient sample, a conclusive analysis on obesity as risk factors for adverse events after endovascular treatment is not possible. A larger sample from the collaboration of multiple centers will be required to obtain definitive conclusions.

Association of Nonmelanoma Skin Cancers, Melanoma, and Merkel Cell Carcinoma with Dermatologic Medications: A Case-Control Pharmacovigilance Study of the FDA Adverse Events Reporting System

Background: Medications used in the treatment of dermatologic conditions have been associated with squamous cell carcinoma (SCC), basal cell carcinoma (BCC), melanoma, and Merkel cell carcinoma (MCC). Objective: The objective of the study was to examine the relationship between systemic dermatologic medications and skin cancer in the FDA Adverse Event Reporting System (FAERS). Methods: Case-control analyses were performed in FAERS from 1968 to 2021 to examine the reporting odds ratios (RORs) for SCC, BCC, melanoma, and MCC. Results: The oral immunosuppressants were all associated with increased ROR of SCC, BCC, melanoma, and MCC. Azathioprine had the highest ROR for SCC (34.13, 95% CI 29.07–40.08), BCC (21.15, 95% CI 20.63–25.98), and MCC (44.76, 95% CI 31.52–63.55), while quinacrine and guselkumab had the highest ROR for melanoma (13.14, 95% CI 1.84–93.89 vs. 12.73, 95% CI 10.60–15.30, respectively). The TNF-α inhibitors were associated with an increased ROR for all skin cancers investigated. Conclusions: The oral immunosuppressants and many biologic medications were associated with an increased ROR of skin cancers including TNF-α inhibitors (etanercept, adalimumab, infliximab), IL-23 or IL-12/23 inhibitors (ustekinumab, risankizumab), and the CD-20 inhibitor rituximab but not dupilumab or IL-17 inhibitors.

Optical Coherence Tomography Angiography Assessment in Congenital Aniridia

This study aims to characterize foveal vasculature assessed by optical coherence tomography angiography (OCT-A) in congenital aniridia which is hallmarked by foveal hypoplasia (FH). Cross-sectional case-control analysis. At the National Referral Center for congenital aniridia, patients with confirmed PAX6-related aniridia and FH diagnosed on spectral-domain OCT (SD-OCT) with available OCT-A and matched control subjects were included. OCT-A was performed in patients with aniridia and control subjects. Foveal avascular zone (FAZ) and vessel density (VD) were collected. VD in the foveal and parafoveal areas at the level of the superficial and deep capillary plexi (SCP and DCP, respectively) were compared between the 2 groups. In patients with congenital aniridia, correlation between VD and the grading of FH was assessed. Among 230 patients with confirmed PAX6-related aniridia, high-quality macular B-scans and OCT-A were available in 10 patients. On the foveal area, mean VD was higher in aniridia patients (41.10%, n=10) than in control subjects (22.65%, n=10) at the level of the SCP and the DCP (P=.0020 and P=.0273, respectively). On the parafoveal area, mean VD was lower in patients with aniridia (42.34%, n=10) than in healthy subjects (49.24%, n=10) at the level of both plexi (P=.0098 and P=.0371, respectively). In patients with congenital aniridia, a positive correlation was found between the grading of FH and the foveal VD at the SCP (r=0.77, P=.0106). Vasculature is altered in PAX6-related congenital aniridia, higher in foveal and lower in parafoveal areas, especially when FH is severe, which is consistent with the concept that the absence of retinal blood vessels is essential for foveal pit development.

Effectiveness of Booster Doses of Monovalent mRNA COVID-19 Vaccine Against Symptomatic Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Children, Adolescents, and Adults During Omicron Subvariant BA.2/BA.2.12.1 and BA.4/BA.5 Predominant Periods.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) BA.2/BA.2.12.1 and BA.4/BA.5 subvariants have mutations associated with increased capacity to evade immunity when compared with prior variants. We evaluated mRNA monovalent booster dose effectiveness among persons ≥5 years old during BA.2/BA.2.12.1 and BA.4/BA.5 predominance. A test-negative, case-control analysis included data from 12 148 pharmacy SARS-CoV-2 testing sites nationwide for persons aged ≥5 years with ≥1 coronavirus disease-2019 (COVID-19)-like symptoms and a SARS-CoV-2 nucleic acid amplification test from April 2 to August 31, 2022. Relative vaccine effectiveness (rVE) was estimated comparing 3 doses of COVID-19 mRNA monovalent vaccine to 2 doses; for tests among persons ≥50 years, rVE estimates also compared 4 doses to 3 doses (≥4 months since third dose). A total of 760 986 test-positive cases and 817 876 test-negative controls were included. Among individuals ≥12 years, rVE of 3 versus 2 doses ranged by age group from 45% to 74% at 1-month post vaccination and waned to 0% by 5-7 months post vaccination during the BA.4/BA.5 period.Adults aged ≥50 years (fourth dose eligible) who received 4 doses were less likely to have symptomatic SARS-CoV-2 infection compared with those with 3 doses; this rVE remained >0% through at least 3 months since last dose. For those aged ≥65 years, rVE of 4 versus 3 doses 1-month post vaccination was higher during BA.2/BA.2.12.1 (rVE = 49%; 95% confidence interval [CI], 43%-53%) than BA.4/BA.5 (rVE = 40%; 95% CI, 36%-44%). In 50- to 64-year-olds, rVE estimates were similar. Monovalent mRNA booster doses provided additional protection against symptomatic SARS-CoV-2 infection during BA.2/BA.2.12.1 and BA.4/BA.5 subvariant circulation, but protection waned over time.

Empirical analysis of traffic flow characteristics at variable approach lanes

It is interesting that despite its long-term and widespread use in China, relatively little is known about the operational characteristics of a variable approach lane (VAL) in real world. Using one month of inductive-loop detector data at ten dynamic approaches (intersection approaches with dynamic lane assignment) from different intersections in Hangzhou, China, this paper presents the results of a study materializing the flow characteristics of variable approach lanes by comparing them with adjacent normal-flow lanes under various operating conditions. The effectiveness of the results was examined in a case-control analysis by integrating 12 fixed approaches (without variable lane) as benchmark. It was found that the difference or similarity of flow rate between the variable lane and the normally-flowing lane differs under a variety of traffic volume, time-of-day, mode-of-operation, and overhead lane-use guidance sign (OHS) location conditions. The study also revealed that while naturally there may be a difference in the flow rates between referencing lanes at fixed approaches, the flow difference percentage (FDP) at dynamic approaches is significantly higher.

Preoperative Dyeing Technique for Decreasing Radiation Exposure in Unilateral Biportal Endoscopic Spine Surgery

Minimally invasive surgery has many advantages, including early recovery and cosmetic preservation. However, the higher radiation exposure to physicians and patients has drawbacks. Preoperative tissue dyeing techniques are feasible options for reducing radiation exposure and procedure time, but their efficacy has not yet been evaluated. Therefore, this study aimed to evaluate surgical outcomes and reduce radiation exposure during unilateral biportal endoscopy surgery. This was a prospective, case-controlled analysis in a tertiary hospital. Patients receiving experimental tissue dye and controls in the nondye group were compared from May 2020 to September 2021. The ipsilateral posterolateral approach (IPA) and the far lateral approach (FLA) were analyzed separately among all single-level spinal procedures without instrumentation. Operative details (operation time, improvement of back and leg pain, and length of hospital stay) and radiation exposure (dose and duration) were compared. A total of 88 cases were included, consisting of 64 interlaminar approaches (experimental: 33, control: 31) and 24 FLAs (experimental: 13 and control: 11). In the IPA approach, the patient and physician radiation exposure doses and duration decreased significantly. Conversely, for the FLA, only the duration of the physician exposure decreased significantly. Preoperative tissue dyeing techniques using IPA can reduce radiation exposure for physicians and patients. However, a decrease in the duration of radiation was observed only in physicians using the FLA. The dyeing technique is effective in IPA, but the efficacy of FLA is doubtful.

Abstract 1183: Mutation type and location in breast cancer susceptibility genes are associated with differential risk in the general population

Abstract Two recent studies have defined population-based risk of breast cancer (BC) due to pathogenic variants (PVs) in well-established BC susceptibility genes. Prior studies in high-risk BC cohorts identified variable BC risks based on the position and type of mutation in BRCA1 and BRCA2, and based on the type of mutation in ATM, CHEK2, and PALB2. Whether this variability holds true in the general population has not been evaluated. To determine the BC risks associated with mutations of different types and in different locations in BC susceptibility genes in the general population, we carried out case-control analyses of 32247 cases and 32544 controls in the CARRIERS study, including 12 US population-based studies, and case-control analyses, subset to mutation carriers. We used age-adjusted logistic regression to estimate odds ratios (OR), relative OR (rOR), and 95% confidence intervals (CI) for PVs in BRCA1, BRCA2, ATM, CHEK2, and PALB2. ORs were estimated using the full population of mutation carriers and noncarriers while rORs were estimated within subsets of individual gene mutation carriers. We identified 273 BRCA1, 421 BRCA2, 253 ATM, 351 CHEK2, and 148 PALB2 in women with BC and 35 BRCA1, 84 BRCA2, 139 ATM, 139 CHEK2, and 38 PALB2 variant carriers in those without BC. For BRCA1, we did not find differences in risk by mutation type or location. However, variants leading to nonsense mediated decay (NMD) predicted to have re-initiation at p.M128 had a non-statistical 3-fold higher risk for BC compared to those leading to NMD without re-initiation (rOR 3.1, 0.99-13.52, p = 0.0826). BRCA2 loss of function (LoF) mutations in exons 1-10 had a higher BC risk compared to LoF mutations in the exon 11 (rOR 2.7, 1.1-7.9, p=0.048) ovarian cancer cluster region (OCCR). We did not detect any differences in risk by mutation type or location in ATM, CHEK2, or PALB2. CHEK2 missense variants p.I157T (rOR 0.5, 0.4-0.7, p &amp;lt;0.001) and p.T476M (rOR 0.5, 0.3 - 0.8, p=0.005) were associated with lower BC risk relative to CHEK2 c.1100delC (OR 2.5, 2.0-3.3, p&amp;lt;0.001). The CHEK2 c.444+1G&amp;gt;A splicing variant was associated with highest BC risk among common CHEK2 variants (OR 4.2, 1.9-10.5, p&amp;lt;0.001), but was not statistically significantly different from c.1100delC (rOR 1.7, 0.8-4.3, p=0.230). In summary, we identified a higher BC risk for LoF variants in BRCA2, lower risk for CHEK2 missense mutations, and non-statistical higher risk for NMD/re-initiation BRCA1 variants and CHEK2 c.444+1G&amp;gt;A in this population-based study. Despite the large numbers included in the overall CARRIERS study, the number of PV carriers was relatively small, which may have limited the detection of associations. Nonetheless, we were able to detect genotype-risk associations that have implications for counseling women about their BC risk, and certainly for the development of individualized risks. Citation Format: Mwangala P. Akamandisa, Nicholas Boddicker, Chunling Hu, Siddhartha Yadav, Jeffrey N. Weitzel, Peter Kraft, Susan M. Domchek, Fergus J. Couch, Katherine L. Nathanson, for the CARRIERS Consortium . Mutation type and location in breast cancer susceptibility genes are associated with differential risk in the general population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1183.

Abstract 230: Characterizing pathogenic germline variants in a large Chinese lung cancer cohort

Abstract Objective: To characterize germline pathogenic/likely pathogenic variants (GPVs) in Chinese lung cancer patients and analyze the prevalence of the GPVs and their association with lung cancer risk as well as various clinical and genomic features. Methods: A total of 17,904 Chinese lung cancer patients were included in the study. Samples of all 17,904 patients were subjected to next-generation targeted sequencing by using a panel covering more than 400 cancer genes, of which 146 are known cancer predisposition genes. Baseline somatic mutations of 5,460 patients were also obtained by targeted sequencing. Germline variants were called from white blood cells, and the GPVs were determined according to the 2015 ACMG Guideline. The prevalence of the GPVs as well as corresponding pathways in the whole cohort and in various subgroups was compared. The odds ratios of the GPVs for lung cancer risk were estimated by case-control analysis based on the local cohort and the gnomAD East Asia database. Interaction between GPVs and somatic mutations was investigated. Results: Among 17,904 patients, 1,738 patients (9.7%) carried 1,840 GPVs from 87 cancer susceptibility genes. SBDS (1.37%), TSHR (1.20%), BLM (0.62%), BRCA2 (0.62%) and ATM (0.45%) were the top 5 genes with the highest prevalence in the whole cohort. GPVs in thirteen genes including FANCF, KIT, LHCGR, MAP2K2, NRAS, etc. have not been reported in lung cancer patients previously. GPVs in certain genes showed histological variation. GPVs in PTEN, BRCA2, WRN, RAD51C, JAK2 and ERBB2 were more enriched in lung squamous cell carcinoma compared with lung adenocarcinoma (LUAD). At pathway level, homologous recombination repair (HRR, 2.09%), TP53 pathway (0.83%), nucleotide excision repair (NER, 0.7%), Fanconi anemia (FA, 0.6%) and DNA damage sensor (0.53%) ranked the first 5 pathways with the highest overall prevalence. Case-control analysis showed SBDS c.184A&amp;gt;T(p.K62*) had the highest odds ratio for lung cancer risk (OR=14.42, P&amp;lt;0.001), followed by JAK2 c.1849G&amp;gt;T(p.V617F)(OR=10.8, P=0.002) and MUTYH c.55C&amp;gt;T(p.R19*)(OR=9.77, P=0.004). The rate of second hit was 4.74% in 464 patients with germline alterations in tumor suppressor genes. Patients with second hit had a higher percentage with family cancer history (68.2% vs. 35.2%, P=0.011), and tumors with second hit showed higher tumor mutation burden (P=3.2e-05) and chromosome instability score (CIS, P=0.12). PGVs in certain genes were associated with early onset of lung cancer, and co-occurrence analysis showed there existed germline-somatic mutation interaction in lung cancer. Conclusion: Chinese lung cancer patients have a relatively high carry rate of PGVs. PGVs are distributed in multiple pathways and dominated by DNA damage repair associated pathways. The association between identified PGVs and lung cancer risk requires further studies to verify. Citation Format: Xiaoying Wu, Xiaojun Fan, Jiaohui Pang, Hua Bao, Jiani Yin, Haimeng Tang, Xue Wu, Yang Shao. Characterizing pathogenic germline variants in a large Chinese lung cancer cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 230.

Abstract 1181: Etiologic heterogeneity of genetic risk for DLBCL cell-of origin molecular subtypes

Abstract Diffuse large B-cell lymphoma (DLBCL) is clinically and biologically heterogenous. Based on gene expression profiling of the tumor, DLBCL is classified into two major molecular subtypes linked to cell-of-origin (COO): germinal center (GCB) and activated B-Cell (ABC). The GCB subtype is characterized by a high prevalence of somatic mutations, particularly in apoptosis genes (e.g., BCL2) which is characteristic of follicular lymphoma (FL, another GCB lymphoma). The development of the validated NanoString gene expression test as well as immunohistochemistry markers that work in formalin-fixed, paraffin-embedded tissue allows for the classification of DLBCL by COO in epidemiological studies. We hypothesized that integration of COO with germline genetics could provide insight into the underlying biology driving this heterogeneity, as well as insight into putative function of germline risk variants. Prior genome wide association studies (GWAS) have identified 7 SNPs in 6 susceptibility loci for DLBCL, including: 2p23.3 (rs79480871 NCOA1), 3q13.33 (rs9831894 CD86), 3p24.1 (rs6773363 EOMES), 6p21.33 (rs2523607 HLA-B), 6p25.3 (rs116446171 EXOC2), and 8q24.21 (rs13255292 and rs4733601 PVT1 and MYC). Two of these loci were also identified in FL GWAS (different lead SNPs): 6p21.33 (rs3130437) and 8q24.21 (rs13254990 PVT1). Additional published FL susceptibility loci include: 3q28 (rs6444305 LPP), 6p21.32 (rs9268839), 11q23.3 (rs4938573 CXCR5), 11q24.3 (rs4937362 ETS1), and 18q21.33 (rs17749561 BCL2). Here we evaluated whether the published DLBCL/FL loci differ by COO molecular subtypes. We evaluated each of the 14 DLBCL/FL SNPs by case-case (GCB vs. nonGCB DLBCL) and polytomous case-control (GCB, nonGCB, and FL vs. controls) analyses. DLBCL cases were classified into GCB vs. nonGCB based on best available data from NanoString, RNAseq, followed by the Hans algorithm. A total of 778 DLBCL cases (470 GCB and 308 nonGCB), 1,050 FL cases, and 1,383 controls were analyzed. Odds ratios (OR) based on ordinal encoding of each SNP and 95% CI were calculated for each of the comparison groups. The ORs for four GWAS SNPs were significantly elevated in GCB vs. nonGCB DLBCL as well as in FL; two were FL GWAS SNPs from the HLA region (6p21.32 and 6p21.33) and the other two (BCL2 and ETS1) are important in the germinal center program. In contrast, one SNP (EXOC2) was significantly elevated in nonGCB-DLBCL and was not associated with GCB-DLBCL or FL; this SNP is also near IRF4 (MUM1), a gene important in the ABC program. For the remaining SNPs, there were suggestive associations for GCB-DLBCL and FL versus nonGCB DLBCL (CD86, CXCR5); nonGCB-DLBCL vs. GCB-DLBCL and FL (NCOA1, PVT1); and associations that showed no pattern with COO (EOMES, LPP, HLA-B and MYC). These findings provide insight into the shared pathogenesis of FL and GCB-DLBCL to inform etiologic mechanisms and risk assessment. Citation Format: Rosalie Griffin Waller, Dennis P. Robinson, Anne J. Novak, Lisa M. Rimsza, Kerstin Wenzl, Rebecca L. King, Andrew L. Feldman, Matthew J. Maurer, Grzegorz S. Nowakowski, Brian K. Link, Thomas M. Habermann, Susan L. Slager, James R. Cerhan. Etiologic heterogeneity of genetic risk for DLBCL cell-of origin molecular subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1181.

Abstract 5237: Regulation of genes located in 6q25 by an Indigenous American genetic variant in breast cancer patients from Peru

Abstract Genetic studies in women of Hispanic/Latina origin identified a single nucleotide polymorphism (SNP) in the 6q25 region, rs140068132, that correlates with Indigenous American (IA) ancestry and is protective against BC. The underrepresentation of Latin American populations in public databases has hindered the study of the mechanisms by which this SNP confers a protective effect. We aimed to identify IA germline variants associated with BC risk and to test their association with tumor gene expression in this region. We performed a case-control fine-mapping analysis in the 6q25 region. BC patients part of the PEGEN-BC Study (N=1809) were included as cases and women from a pregnancy outcomes study in Peru as controls (N=3334). Genome-wide genotype data were available and missing genotypes were imputed using the TOPMED Imputation Server. Logistic regression was used to test the association between each SNP and BC risk. We exome-sequenced 247 breast tumors of PEGEN-BC patients. Tumor subtype was assigned by the pam50 method. We excluded patients diagnosed with stage IV disease, with tumors classified as normal-like or as uncertain, and carriers of the GG genotype for rs140068132, leaving 242 samples. Association between rs140068132 and gene expression of genes in the 6q25 region was tested adjusting by age at diagnosis and IA ancestry. The strongest signal corresponded to rs140068132 (odds ratio (OR)=0.53, p=1.9e-21). The model adjusted by rs140068132 revealed three additional independent variants that correlate with Indigenous American ancestry: rs184135739 (OR=0.8, p=0.006), rs141057867 (OR=0.87, p=0.006) and rs140125124 (OR=1.23, p=0.015). Gene expression analysis stratified by subtype revealed that among HER2+ tumors (N=63), rs140068132 was associated with ARMT1 (fold change comparing AA to AG (FC)=1.6, p&amp;lt;0.01), CCDC170 (FC=1.8, p&amp;lt;0.01), MTHFD1L (FC=0.7, p&amp;lt;0.01) and RMND1 (FC=1.4, p=0.013). Among Luminal-B (N=68) tumors, there was an association with ARMT1 (FC= 1.9, p=0.001), ESR1 (FC=1.4, p=0.04) and MTHFD1L (FC= 0.8, p=0.02). Only ESR1 was associated with the SNP (FC= 0.5, p= 0.03) among basal tumors (N=56). No association was identified among Luminal-A tumors (N=55). rs141057867 showed evidence of cis-association with CLDN20 (FC=1.4, p=0.014) among HER2+ subtypes and rs184135739 with ZC3H12D (FC=2.1, p=0.02) and SUMO4 (FC=1.8, p=0.023) among Lumina-A tumors. Two of the three novel IA SNPs are protective against BC and show association with gene expression. The rs140068132-G variant regulates the expression of genes in the 6q25 region in a subtype-specific manner. A possible mechanism explaining the protective effect of the rs140068132 polymorphism might be linked to the lower expression of MTHFD1L among G-allele carriers in some subtypes. This gene is deregulated in cancer and its expression is negatively associated with cancer survival, including BC. Citation Format: Valentina A. Zavala, Xiaosong Huang, Sandro Casavilca-Zambrano, Jeannie Navarro-Vásquez, Carlos A. Castañeda, Guillermo Valencia, Zaida Morante, Monica Calderon, Julio E. Abugattas, Henry Gómez, Hugo Fuentes, Ruddy Liendo-Picoaga, Jose M. Cotrina, Katia Roque, Jule Vásquez, Luis Mas, Marco Gálvez-Nino, Jovanny Zabaleta, Tatiana Vidaurre, Laura Fejerman. Regulation of genes located in 6q25 by an Indigenous American genetic variant in breast cancer patients from Peru. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5237.

Abstract 5229: Pathogenic germline mutations and risk of multiple myeloma

Abstract BACKGROUND: Multiple Myeloma (MM) is an incurable disease with no known germline high penetrant risk gene. The higher risk of MM among affected relatives suggests a genetic contribution to the etiology. To date, 24 common risk variants with low effect sizes were identified using genome-wide association studies, which account for 17% of heritability. However, a systematic analysis of the known rare alleles in cancer predisposition genes has not been undertaken so far in MM. We collaborated with six other academic centers across the United States to identify and select cases for analysis of germline predisposition of MM. METHODS: We performed whole exome, next-generation sequencing of 2,387 familial or early onset germline MM cases from the myeloma sequencing consortium (MMSEQ). We called 1.5 million variants and performed standard quality control of the data. We also obtained exome data on 1,285 cases from UK Biobank (UKBB) and 344,513 non-cancer controls (total=3,672 cases). We analyzed the ultra-rare, coding variants in 90 clinically relevant or putative candidates for cancer predisposition. We then used the automated variant curator PathoMAN to annotate and assert pathogenicity of each variant. We contrasted our results with assertions of pathogenicity from ClinVar and tested for gene association with MM. RESULTS: Overall, we observed several pathogenic or likely pathogenic variants, both singleton and recurrent founder mutations. In the MMSEQ, 8.7% of MM cases harbored a pathogenic variant in these known/putative cancer predisposition genes. Predominant group of pathogenic variants were observed within CHEK2 (19%), TP53 (8%), and ATM (5%). A case-control analysis revealed strong association with TP53 and weakly with ATM. In the familial/early onset MMSEQ cases, TP53 mutations were enriched 68 times more than in the UKBB controls. Our preliminary results suggest that known genes of cancer susceptibility such as TP53 and ATM may also play a role in myeloma risk. CONCLUSION: In a large study of multi-center MM cases, we identified a significant proportion of individuals who are carriers of known (solid) cancer predisposition genes. This study suggests that these known cancer predisposition genes may be relevant in a subset of MM cases. Citation Format: Michael T. Conry, Nicola Camp, Celine Vachon, Michelle Hildebrandt, Elizabeth E. Brown, Steven M. Lipkin, Judy Garber, Susan L. Slager, Samantha Stokes, Aaron D. Norman, Aalin Izhar, Sita Dandiker, Kylee Maclachlan, Kenneth Offit, Saad Usmani, Vijai Joseph. Pathogenic germline mutations and risk of multiple myeloma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5229.

MP69-02 CLINICAL IMPACT OF CANCER PREDISPOSING GENES ON UPPER URINARY TRACT UROTHELIAL CARCINOMA: A LARGE SCALE GENOME ANALYSIS IN JAPAN

You have accessJournal of UrologyCME1 Apr 2023MP69-02 CLINICAL IMPACT OF CANCER PREDISPOSING GENES ON UPPER URINARY TRACT UROTHELIAL CARCINOMA: A LARGE SCALE GENOME ANALYSIS IN JAPAN Yuya Sekine, Yusuke Iwasaki, Mikiko Endo, Takeshi Sano, Shusuke Akamatsu, Takashi Kobayashi, Hidewaki Nakagawa, Kazuyuki Numakura, Shintaro Narita, Yukihide Momozawa, and Tomonori Habuchi Yuya SekineYuya Sekine More articles by this author , Yusuke IwasakiYusuke Iwasaki More articles by this author , Mikiko EndoMikiko Endo More articles by this author , Takeshi SanoTakeshi Sano More articles by this author , Shusuke AkamatsuShusuke Akamatsu More articles by this author , Takashi KobayashiTakashi Kobayashi More articles by this author , Hidewaki NakagawaHidewaki Nakagawa More articles by this author , Kazuyuki NumakuraKazuyuki Numakura More articles by this author , Shintaro NaritaShintaro Narita More articles by this author , Yukihide MomozawaYukihide Momozawa More articles by this author , and Tomonori HabuchiTomonori Habuchi More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003332.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Quite a few numbers of upper urinary tract urothelial carcinoma (UTUC) would be caused by germline pathogenic variants. Although mismatch repair (MMR) genes are known for pathogenicity for UTUC, the impact of other cancer-predisposing genes, such as BRCA1/2, on UTUC has never been thoroughly investigated despite the fact that panel sequencing is a standard method for advanced cancers. We conducted a case-control genetic analysis to clarify the association between these possible genes and UTUC in Japanese. METHODS: We enrolled 210 patients with UTUC and 38,300 general subjects from Biobank Japan as controls. Twenty-seven genes were sequenced, including cancer-predisposing genes such as MMRs and BRCA1/2. Pathogenic variants were defined as follows; loss-of-function variants or variants registered as pathogenic in ClinVar. RESULTS: After quality control, 209 patients with UTUC and 37,727 controls were analyzed. In the 27 analyzed genes, 4,769 germline variants, including 286 pathogenic variants, were confirmed. The pathogenic variants in MMR genes were detected in 1.44% of patients with UTUC and significantly associated with conceiving the UTUC (p=1.30×10-3, OR 15.24). In the other genes, BRCA1 and BRCA2 had only one patient with pathogenic variants, and no significant association was verified. CONCLUSIONS: The significant association was observed between MMR genes and the prevalence of UTUC in Japanese. Other cancer-predisposing genes were not associated with UTUC in our study. It needs more patients to know whether these genes affect the risk of UTUC. Source of Funding: Japan Agency for Medical Research and Development (AMED) under Grant No. JP19kk0305010 © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e963 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yuya Sekine More articles by this author Yusuke Iwasaki More articles by this author Mikiko Endo More articles by this author Takeshi Sano More articles by this author Shusuke Akamatsu More articles by this author Takashi Kobayashi More articles by this author Hidewaki Nakagawa More articles by this author Kazuyuki Numakura More articles by this author Shintaro Narita More articles by this author Yukihide Momozawa More articles by this author Tomonori Habuchi More articles by this author Expand All Advertisement PDF downloadLoading ...