Population-based Controls Research Articles

Risk factors in children with optic nerve hypoplasia and septo-optic dysplasia.

To identify the risk factors for optic nerve hypoplasia (ONH) and septo-optic dysplasia (SOD). A retrospective, population-based study with case-control design was undertaken using the Population Research Data Repository at the Manitoba Center for Health Policy in Manitoba, Canada. Cases were 111 patients (63 males, 48 females; age range 1-35 years [mean 11 years 6 months, SD 7 years 2 months]) with ONH and SOD diagnosed from 1990 to 2019, matched to 555 unrelated population-based controls (315 males, 240 females; age range 1-35 years [mean 11 years 6 months, SD 7 years 2 months]) on year of birth, sex, and area of residence. Additionally, 75 cases (46 males, 29 females; age range 2-35 years [mean 12 years 6 months, SD 7 years 2 months]) with ONH and SOD were matched one-on-one with sibling controls (40 males, 35 females; age range 0-33 years[mean 11 years 7 months, SD 7 years 10 months], the rest did not have siblings). Several antenatal maternal risk factors associated with ONH and SOD were tested for their association with case and control group membership using adjusted odds ratios (ORs) and 95% confidence intervals (CIs) from a multivariate conditional logistic regression model. The outcome was the risk of developing ONH and SOD. Maternal age at conception (OR = 0.91, 95% CI = 0.86-0.96), primigravida (OR = 3.39, 95% CI = 1.92-6.01), and smoking (OR = 2.86, 95% CI = 1.61-5.05) were independently associated with ONH and SOD in the cohort matched to unrelated controls (p < 0.001). In the sibling cohort, smoking was an important risk factor (OR = 3.65, 95% CI = 1.2-11.1, p = 0.02). Unmodifiable and modifiable antenatal maternal risk factors are associated with ONH and SOD. Our investigation suggests that several risk factors reported in previous studies may have been due to confounding bias and that maternal smoking during pregnancy is the main modifiable risk factor associated with ONH and SOD. Historically, many antenatal risk factors have been associated with optic nerve hypoplasia (ONH) and septo-optic dysplasia (SOD). Population-based data with matched controls for potential confounding bias are lacking. Young maternal age at conception, primigravida, and smoking during pregnancy are the main risk factors for ONH and SOD using a population-based, case-control design.

Risks of alcohol and drug use disorders in prostate cancer survivors: a national cohort study.

Prostate cancer (PC) survivors may potentially use substances to cope with psychological distress or poorly controlled physical symptoms. Little is known, however, about the long-term risks of alcohol use disorder (AUD) or drug use disorders in men with PC. A national cohort study was conducted in Sweden of 180 189 men diagnosed with PC between 1998 and 2017 and 1 801 890 age-matched population-based control men. AUD and drug use disorders were ascertained from nationwide records through 2018. Cox regression was used to compute hazard ratios (HRs) while adjusting for sociodemographic factors and prior psychiatric disorders. Subanalyses examined differences by PC treatment from 2005 to 2017. Men with high-risk PC had increased risks of both AUD (adjusted HR = 1.44, 95% confidence interval [CI] = 1.33 to 1.57) and drug use disorders (adjusted HR = 1.93, 95% CI = 1.67 to 2.24). Their AUD risk was highest in the first year and was no longer significantly elevated 5 years after PC diagnosis, whereas their drug use disorders risk remained elevated 10 years after PC diagnosis (adjusted HR = 2.26, 95% CI = 1.45 to 3.52), particularly opioid use disorder (adjusted HR = 3.07, 95% CI = 1.61 to 5.84). Those treated only with androgen-deprivation therapy had the highest risks of AUD (adjusted HR = 1.91, 95% CI = 1.62 to 2.25) and drug use disorders (adjusted HR = 2.23, 95% CI = 1.70 to 2.92). Low- or intermediate-risk PC was associated with modestly increased risks of AUD (adjusted HR = 1.38, 95% CI = 1.30 to 1.46) and drug use disorders (adjusted HR = 1.19, 95% CI = 1.06 to 1.34). In this large cohort, men with PC had significantly increased risks of both AUD and drug use disorders, especially those with high-risk PC and treated only with androgen-deprivation therapy. PC survivors need long-term psychosocial support and timely detection and treatment of AUD and drug use disorders.

Children at Familial High risk of Schizophrenia and Bipolar Disorder Exhibit Altered Connectivity Patterns During Pre-attentive Processing of an Auditory Prediction Error.

Individuals with schizophrenia or bipolar disorder have attenuated auditory mismatch negativity (MMN) responses, indicating impaired sensory information processing. Computational models of effective connectivity between brain areas underlying MMN responses show reduced connectivity between fronto-temporal areas in individuals with schizophrenia. Here we ask whether children at familial high risk (FHR) of developing a serious mental disorder show similar alterations. We recruited 67 children at FHR for schizophrenia, 47 children at FHR for bipolar disorder as well as 59 matched population-based controls from the Danish High Risk and Resilience study. The 11-12-year-old participants engaged in a classical auditory MMN paradigm with deviations in frequency, duration, or frequency and duration, while we recorded their EEG. We used dynamic causal modeling (DCM) to infer on the effective connectivity between brain areas underlying MMN. DCM yielded strong evidence for differences in effective connectivity among groups in connections from right inferior frontal gyrus (IFG) to right superior temporal gyrus (STG), along with differences in intrinsic connectivity within primary auditory cortex (A1). Critically, the 2 high-risk groups differed in intrinsic connectivity in left STG and IFG as well as effective connectivity from right A1 to right STG. Results persisted even when controlling for past or present psychiatric diagnoses. We provide novel evidence that connectivity underlying MMN responses in children at FHR for schizophrenia and bipolar disorder is altered at the age of 11-12, echoing findings that have been found in individuals with manifest schizophrenia.

Associations between birth defects and childhood and adolescent germ cell tumors according to sex, histologic subtype, and site.

Studies have reported increased rates of birth defects among children with germ cell tumors (GCTs). However, few studies have evaluated associations by sex, type of defect, or tumor characteristics. Birth defect-GCT associations were evaluated among pediatric patients (N = 552) with GCTs enrolled in the Germ Cell Tumor Epidemiology Study and population-based controls (N = 6380) without cancer from the Genetic Overlap Between Anomalies and Cancer in Kids Study. The odds ratio (OR) and 95% confidence interval (CI) of GCTs according to birth defects status were estimated by using unconditional logistic regression. All defects were considered collectively and by genetic and chromosomal syndromes and nonsyndromic defects. Stratification was by sex, tumor histology (yolk sac tumor, teratoma, germinoma, and mixed/other), and location (gonadal, extragonadal, and intracranial). Birth defects and syndromic defects were more common among GCT cases than controls (6.9% vs. 4.0% and 2.7% vs. 0.2%, respectively; both p < .001). In multivariable models, GCT risk was increased among children with birth defects (OR, 1.7; 95% CI, 1.3-2.4) and syndromic defects (OR, 10.4; 95% CI, 4.9-22.1). When stratified by tumor characteristics, birth defects were associated with yolk sac tumors (OR, 2.7; 95% CI, 1.3-5.0) and mixed/other histologies (OR, 2.1; 95% CI, 1.2-3.5) and both gonadal tumors (OR, 1.7; 95% CI, 1.0-2.7) and extragonadal tumors (OR, 3.8; 95% CI, 2.1-6.5). Nonsyndromic defects specifically were not associated with GCTs. In sex-stratified analyses, associations were observed among males but not females. These data suggest that males with syndromic birth defects are at an increased risk of pediatric GCTs, whereasmales with nonsyndromic defects and females are not at an increased risk. We investigated whether birth defects (such as congenital heart disease or Down syndrome) are linked to childhood germ cell tumors (GCTs), cancers that mainly develop in the ovaries or testes. We studied different types of birth defects (defects that were caused by chromosome changes such as Down syndrome or Klinefelter syndrome and defects that were not) and different types of GCTs. Only chromosome changes such as Down syndrome or Klinefelter syndrome were linked to GCTs. Our study suggests that most children with birth defects are not at an increased risk of GCTs because most birth defects are not caused by chromosome changes.

Ability of a polygenic risk score to refine colorectal cancer risk in Lynch syndrome

BackgroundPolygenic risk scores (PRSs) have been used to stratify colorectal cancer (CRC) risk in the general population, whereas its role in Lynch syndrome (LS), the most common type of hereditary...

Attachment representations in 7-year-old children at familial high risk of schizophrenia or bipolar disorder: Associations with mental disorders and daily functioning: The Danish High Risk and Resilience Study, VIA 7-A population-based cohort study.

Attachment quality may affect psychological functioning. However, evidence on attachment representations and their correlates in children born to parents with schizophrenia and bipolar disorder is sparse. We compared attachment representations in a Danish sample of 482 children aged 7 years at familial high risk of schizophrenia, bipolar disorder, and population-based controls and examined associations between attachment and mental disorders and daily functioning. Attachment representations were examined with the Story Stem Assessment Profile (SSAP). Mental disorders were ascertained in diagnostic interviews. Daily functioning was assessed with the Children's Global Assessment Scale. We found no between-group differences in attachment. Higher levels of secure attachment were associated with decreased risk of concurrent mental disorders in the schizophrenia high-risk group. Higher levels of insecure and disorganized attachment were associated with increased risk of mental disorders across the cohort. Higher levels of secure and insecure attachment were associated with better and poorer daily functioning, respectively. In the current study, results regarding defensive avoidance could not be reported due to methodological limitations. Familial high risk of schizophrenia (FHR-SZ) or bipolar disorder is not associated with less secure or more insecure attachment at age 7. Insecure and disorganized attachment representations index risk of mental disorders and poorer functioning. Secure attachment may be a protective factor against mental disorders in children at FHR-SZ. Validation of the SSAP is needed.

Traditional Chinese medicine use is associated with lower risk of pneumonia in patients with systemic lupus erythematosus: a population-based retrospective cohort study.

Objectives: To investigate the association between traditional Chinese medicine (TCM) therapy and the risk of pneumonia in patients with systemic lupus erythematosus (SLE). Methods: This population-based control study analyzed the data retrieved from the National Health Insurance Research database in Taiwan. From a cohort of 2 million records of the 2000-2018 period, 9,714 newly diagnosed patients with SLE were initially included. 532 patients with pneumonia and 532 patients without pneumonia were matched 1:1 based on age, sex, and year of SLE diagnosis using propensity score matching. The use of TCM therapy was considered from the SLE diagnosis date to the index date and the cumulative days of TCM therapy were used to calculate the dose effect. Conditional logistic regression was used to investigate the risk of pneumonia infection. Furthermore, to explore the severity of pneumonia in SLE, sensitivity analyses were performed after stratification using the parameters of emergency room visit, admission time, and antibiotic use. Results: TCM therapy for >60days could significantly reduce the risk of pneumonia in patients with SLE (95% CI = 0.46-0.91; p = 0.012). Stratified analysis showed that TCM use also reduced the risk of pneumonia in younger and female patients with SLE by 34% and 35%, respectively. TCM for >60days significantly reduced the risk of pneumonia in the follow-up periods of >2, >3, >7, and >8years. In addition, the exposure of TCM for >60days reduced the risk of pneumonia in patients with SLE who were treated with antibiotics for moderate or severe pneumonia. Finally, the study found that using formulae to tonify the kidney for more than 90days and formulae to activate blood circulation for less than 30days could significantly reduce the risk of pneumonia infection in patients with SLE. Conclusion: TCM use is associated with a lower risk of pneumonia among patients with SLE.

Development and internal validation of a multifactorial risk prediction model for gallbladder cancer in a high-incidence country.

Since 2006, Chile has been implementing a gallbladder cancer (GBC) prevention program based on prophylactic cholecystectomy for gallstone patients aged 35 to 49 years. The effectiveness of this prevention program has not yet been comprehensively evaluated. We conducted a retrospective study of 473 Chilean GBC patients and 2137 population-based controls to develop and internally validate three GBC risk prediction models. The Baseline Model accounted for gallstones while adjusting for sex and birth year. Enhanced Model I also included the non-genetic risk factors: body mass index, educational level, Mapuche surnames, number of children and family history of GBC. Enhanced Model II further included Mapuche ancestry and the genotype for rs17209837. Multiple Cox regression was applied to assess the predictive performance, quantified by the area under the precision-recall curve (AUC-PRC) and the number of cholecystectomies needed (NCN) to prevent one case of GBC at age 70 years. The AUC-PRC for the Baseline Model (0.44%, 95%CI 0.42-0.46) increased by 0.22 (95%CI 0.15-0.29) when non-genetic factors were included, and by 0.25 (95%CI 0.20-0.30) when incorporating non-genetic and genetic factors. The overall NCN for Chileans with gallstones (115, 95%CI 104-131) decreased to 92 (95%CI 60-128) for Chileans with a higher risk than the median according to Enhanced Model I, and to 80 (95%CI 59-110) according to Enhanced Model II. In conclusion, age, sex and gallstones are strong risk factors for GBC, but consideration of other non-genetic factors and individual genotype data improves risk prediction and may optimize allocation of financial resources and surgical capacity.

A study of the genetic architecture of social responsiveness in families with parental schizophrenia or bipolar disorder and population-based controls

Twin-studies of social responsiveness have reported moderate to high heritabilities, but studies using parent–child data are lacking. Additionally, social impairments have been suggested as a vulnerability marker for schizophrenia and bipolar disorder, but the heritability of social responsiveness in this context is unknown. This study is part of the Danish High Risk and Resilience Study – VIA, comprising families with one parent with schizophrenia (n = 202) or bipolar disorder (n = 120) and population-based controls (PBC, n = 200). Social responsiveness was assessed with The Social Responsiveness Scale, Second Edition (SRS-2). Heritability was estimated from variance components, and a polygenic risk score (PRS) for autism spectrum disorder (ASD) was calculated to assess the genetic relationship between ASD and SRS-2. SRS-2 heritability was moderate to high and significantly different from zero in all groups when the children were rated by the primary caregiver. With teacher ratings, the heritability was lower and only significant in the full cohort and PBC. We found no significant association between SRS-2 and PRS for ASD. Our study confirms that social responsiveness is heritable, but that heritability estimates are affected by the child-respondent relation and familial risk of mental illness. This has implications for clinical practice and research using SRS-2 and provides insight on the familial transmission of mental illness.

Early disc degeneration in radiotherapy-treated childhood brain tumor survivors

BackgroundChildhood brain tumor (BT) survivors have an increased risk of treatment-related late effects, which can reduce health-related quality of life and increase morbidity. This study aimed to investigate lumbar disc degeneration in magnetic resonance imaging (MRI) in adult survivors of radiotherapy-treated childhood BT compared to age and sex-matched population controls.MethodsIn this cross-sectional comparative study, 127 survivors were identified from hospital registries. After a mean follow-up of 20.7 years (range 5–33.1), 67 survivors (mean age 28.4, range 16.2–43.5) were investigated with MRI and compared to 75 sex-matched population-based controls. Evaluated MRI phenotypes included Pfirrmann grading, , intervertebral disc protrusions, extrusions, and high-intensity-zone-lesions (HIZ). Groups were also compared for known risk factors of lumbar intervertebral disc (IVD) degeneration.ResultsChildhood BT survivors had higher Pfirrmann grades than controls at all lumbar levels (all p < 0.001). Lumbar disc protrusions at L4-5 (p = 0.02) and extrusions at L3-4 (p = 0.04), L4-5 (p = 0.004), and L5-S1 (p = 0.01) were significantly more common in the BT group compared to the control. The survivor cohort also had significantly more HIZ-lesons than the controls (n=13 and n=1, p=0.003). Age at diagnosis was associated with lower degree of IVD degeneration (p < 0.01). Blood pressure correlated with IVD degeneration (P < 0.05).ConclusionsSigns of early disc degeneration related to tumor treatment can be seen in the IVDs of survivors. Disc degeneration was more severe in children treated in adolescence.

Antioxidant Nutrients and Risk of Latent Autoimmune Diabetes in Adults and Type 2 Diabetes: A Swedish Case-Control Study and Mendelian Randomization Analysis.

Antioxidant vitamins C and E are inversely associated with type 1 diabetes (T1D). We investigated if antioxidants are also associated with latent autoimmune diabetes in adults (LADA), with low (LADAlow) and high (LADAhigh) autoantibody levels, type 2 diabetes (T2D), and estimates of beta cell function (HOMA-B) and insulin resistance (HOMA-IR). We used Swedish case-control data with incident cases of LADA (n = 584) and T2D (n = 1989) and matched population-based controls (n = 2276). Odds ratios (OR) and 95% confidence intervals (CI) were calculated per one standard deviation higher beta-carotene, vitamin C, vitamin E, selenium, and zinc intakes. Two-sample Mendelian randomization (MR) analyses assessed causality between genetically predicted circulating antioxidants and LADA, T1D, and T2D, using summary statistics from genome-wide association studies. Among the antioxidants, vitamins C and E were inversely associated with LADAhigh (OR 0.84, CI 0.73, 0.98 and OR 0.80, CI 0.69, 0.94 respectively), but not with LADAlow or T2D. Vitamin E was also associated with higher HOMA-B and lower HOMA-IR. MR analyses estimated an OR of 0.50 (CI 0.20, 1.25) for the effect of vitamin E on T1D, but did not support causal relationships between antioxidants and either LADA or T2D. In conclusion, vitamin E may have a protective effect on autoimmune diabetes, possibly through preserved beta cell function and less insulin resistance.

Surviving critical COVID-19 requiring mechanical ventilation is associated with a high long-term risk of de novo arrhythmic events

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Swedish Research Council Swedish Heart- and Lung Foundation Background The long-term risk of de novo arrhythmic events after severe COVID-19 requiring intensive care is largely unknown, especially after adjusting for multiple risk factors such as co-morbidities and socio-economic factors. Objective The primary objective of this study was to investigate the long-term, co-variate adjusted risk of arrhythmic event after discharge from intensive care unit for critical COVID-19. Methods We performed a nationwide case-control study on patients with severe COVID-19 (cases) treated with mechanical ventilation and discharged alive from an intensive care unit. Each case was matched (age, sex, district of residence) with up to 10 population-based control. The study database from the Swedish ICU register was merged with multiple compulsory national registries. The primary outcome was hospitalizations with the following arrhythmias identified: ventricular tachycardia, atrial fibrillation, any other tachy-arrhythmia, or bradycardia/pacemaker implantation. Hazard ratios were adjusted for co-morbidities, socioeconomic status, level of education, region of birth and disposable income. Average follow-up was 12 months. Results We included 3 023 patients with severe COVID-19 that were treated with mechanical ventilation at a Swedish ICU (March 1, 2020 to June 8, 2021) and were discharged alive. Control subjects (n= 28,463 ) were selected based on matching by age, sex and district of residence. The Hazard ratios for the risk of de novo arrhythmic event post ICU discharge for COVID-19 adjusted for age, gender, all comorbidities, level of education, marital status and income were increased between 13.1 – 21.0 in all four types of arrhythmias (Table 1). Conclusions We report increased risks for major arrhythmic events following severe COVID-19 even after adjusting for cardiovascular risk factors and for socio-economic factors. These data suggest that at least patients with inherit risk factors for developing arrhythmias in need of ICU treatment for COVID-19 should be closely followed-up after discharge.

Conversion Rate of Essential Tremor to Essential Tremor Parkinson Disease: Data From a Prospective Longitudinal Study.

There has been a long-standing dialog as to whether essential tremor (ET) increases the risk of developing Parkinson disease (PD). While there are relevant cross-sectional data, there are almost no longitudinal prospective data. We quantified the conversion rate from ET to ETPD in a prospective longitudinal cohort study of patients with ET. We compared the observed rate with that reported in the epidemiologic literature. We enrolled patients with ET in a prospective, longitudinal study. A senior movement disorders neurologist evaluated standardized neurologic examinations every 18 months. One hundred ninety-three patients with ET (mean age = 78.1 ± 9.6 years, range = 55-96) had a mean follow-up duration of 4.1 years. Seven (3.6%) converted from ET to ETPD. The incidence of PD among patients with ET was 7/792.9 person-years (py; i.e., 882.8/100,000 py). A meta-analysis of the incidence (per 100,000 py) of PD in 14 studies from 13 countries across 4 continents reported an incidence of PD = 61.21 (men, 40 years or older) and 37.55 (women, 40 years or older). The incidence/100,000 py in men peaked in the 80- to 89-year-old age group (258.47) and in women in the 80- to 89-year-old age group (103.48 py). The abovementioned published values are 3.4-23.5 times lower than the value we observed for ET. The incidence of PD in an ET cohort is substantially higher than that reported in historical population-based control groups across numerous countries. Additional prospective longitudinal data are needed to further explore this association.

Tinnitus Is Marginally Associated with Body Mass Index, Heart Rate and Arterial Blood Pressure: Results from a Large Clinical Sample.

This study aimed to explore whether body mass index (BMI), systolic blood pressure (RR syst), diastolic blood pressure (RR diast) or heart rate (HR) are associated with tinnitus status and/or severity. To that end, we evaluated the influence of tinnitus status and Tinnitus Handicap Inventory (THI) score on BMI, RR syst, RR diast and HR by comparing data from a large sample of patients presenting to a specialized tertiary referral clinic (N = 1066) with data from a population-based control group (N = 9885) by means of linear models. Tinnitus patients had a significantly lower BMI and higher RR syst, RR diast and HR than non-tinnitus patients; however, the contribution of the case-control status to R2 was very small (0.1%, 0.7%, 1.4% and 0.4%, respectively). BMI had little predictive power for the THI score (higher BMI scores were related to higher THI scores; R2 = 0.5%) and neither RR syst, RR diast, nor HR showed a statistically significant association with THI. Our findings suggest that HR, RR and BMI are at most marginally associated with tinnitus status and severity.

The added effect of non-pharmaceutical interventions and lifestyle behaviors on vaccine effectiveness against severe COVID-19 in Chile: A matched case-double control study.

World Health Organization approved vaccines have demonstrated relatively high protection against moderate to severe COVID-19. Prospective vaccine effectiveness (VE) designs with first-hand data and population-based controls are nevertheless rare. Neighborhood compared to hospitalized controls, may differ in compliance to non-pharmacuetical interventions (NPI) compliance, which may influence VE results in real-world settings. We aimed to determine VE against COVID-19 intensive-care-unit (ICU) admission using hospital and community-matched controls in a prospective design. We conducted a multicenter, observational study of matched cases and controls (1:3) in adults ≧18 years of age from May to July 2021. For each case, a hospital control and two community controls were matched by age, gender, and hospital admission date or neighborhood of residence. Conditional logistic regression models were built, including interaction terms between NPIs, lifestyle behaviors, and vaccination status; the model's β coefficients represent the added effect these terms had on COVID-19 VE. Cases and controls differed in several factors including education level, obesity prevalence, and behaviors such as compliance with routine vaccinations, use of facemasks, and routine handwashing. VE was 98·2% for full primary vaccination and 85·6% for partial vaccination when compared to community controls, and somewhat lower, albeit not significantly, compared to hospital controls. A significant added effect to vaccination in reducing COVID-19 ICU admission was regular facemask use and VE was higher among individuals non-compliant with the national vaccine program, and/or tonroutine medical visits during the prior year. VE against COVID-19 ICU admission in this stringent prospective case-double control study reached 98% two weeks after full primary vaccination, confirming the high effectiveness provided by earlier studies. Face mask use and hand washing were independent protective factors, the former adding additional benefit to VE. VE was significantly higher in subjects with increased risk behaviors.

Risk factors for severe COVID-19 in the young—before and after ICU admission

BackgroundFactors associated with severe COVID-19 and death among young adults are not fully understood, including differences between the sexes. The aim of this study was to identify factors associated with severe COVID-19 requiring intensive care and 90-day mortality among women and men below 50 years of age.MethodsA register-based study using data from mandatory national registers, where patients with severe COVID-19 admitted to the ICU with need for mechanical ventilation (cases) between March 2020 and June 2021 were matched regarding age, sex, and district of residence with 10 population-based controls. Both the study population and the controls were divided into groups based on age (< 50 years, 50–64, and ≥ 65 years) and sex. Multivariate logistic regression models including socioeconomic factors were used to calculate odds ratios (OR) with 95% confidence intervals (CIs) for associations between severe COVID-19 in the population to compare the magnitude of the risk associations for co-morbidities in the different age categories, and subsequently factors associated with 90-day mortality among patients admitted to ICU.ResultsIn total, 4921 cases and 49,210 controls (median age 63 years, 71% men) were included.The co-morbidities with the strongest associations with severe COVID-19 for the young population compared to older patients were chronic kidney disease (OR 6.80 [3.61–12.83]), type 2 diabetes (OR 6.31 [4.48–8.88]), hypertension (OR 5.09 [3.79–6.84]), rheumatoid arthritis (OR 4.76 [2.29–9.89]), obesity (OR 3.76 [2.88–4.92]), heart failure (OR 3.06 [1.36–6.89]), and asthma (OR 3.04 [2.22–4.16]).When comparing women vs. men < 50 years of age, stronger associations were seen for women regarding type 2 diabetes (OR 11.25 [6.00–21.08] vs OR 4.97 [3.25–7.60]) and hypertension (OR 8.76 [5.10–15.01] vs OR 4.09 [2.86–5.86]).The factors associated with 90-day mortality in the young were previous venous thromboembolism (OR 5.50 [2.13–14.22]), chronic kidney disease (OR 4.40 [1.64–11.78]) and type 2 diabetes (OR 2.71 [1.39–5.29]). These associations with 90-day mortality were foremost driven by the female population.ConclusionChronic kidney failure, type 2 diabetes, hypertension, rheumatoid arthritis, obesity, heart failure, and asthma were the strongest risk factors associated with severe COVID-19 requiring ICU-care in individuals < 50 years compared to the older population. However, after ICU admission, previous thromboembolism, chronic kidney failure, and type 2 diabetes were associated with increased 90-day mortality. The risk associations for co-morbidities were generally stronger among younger individuals compared to older and in women compared to men.

Conversion Rate of Essential Tremor to Essential Tremor-Parkinson’s Disease: Data from a Prospective, Longitudinal Study (S42.010)

<h3>Objective:</h3> We quantified the conversion rate from essential tremor (ET) to ET with Parkinson’s disease (ETPD) in a prospective, longitudinal cohort study of ET cases. We compared the observed rate to that reported in the epidemiological literature. <h3>Background:</h3> There has been a longstanding dialogue as to whether ET increases the risk of developing PD. While there are relevant cross-sectional data, there are almost no longitudinal, prospective data. <h3>Design/Methods:</h3> We enrolled ET cases in a prospective, longitudinal study. A senior movement disorders neurologist evaluated standardized neurological examinations every 18 months. <h3>Results:</h3> 193 ET cases (mean age = 78.1 ± 9.6 years, range = 55 – 96) had a mean follow-up duration of 4.1 years. Seven (3.6%) converted from ET to ETPD. The incidence of PD among ET cases was 7/792.9 person years [py] (i.e., 882.8/100,000 py). A meta-analysis of the incidence (per 100,000 py) of PD in 14 studies from 13 countries across 4 continents reported an incidence of PD = 61.21 (males, ≥40 years) and 37.55 (females, ≥40 years). The incidence/100,000 py in males peaked in the 80 – 89 year old age group (258.47) and in females in the 80 – 89 year old age group (103.48 py). The above published values are 3.4 – 23.5 times lower than the value we observed for ET. <h3>Conclusions:</h3> The incidence of PD in an ET cohort is substantially higher than that reported in historical, population-based control groups across numerous countries. Additional prospective, longitudinal data are needed to further explore this association. <b>Disclosure:</b> Dr. Louis has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Wolters Kluwer - Merritt’s Textbook of Neurology. The institution of Dr. Louis has received research support from National Institutes of Health. Dr. Berry has nothing to disclose. Dr. Ghanem has nothing to disclose. Dr. Cosentino has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Association for Frontotemporal Dementia. Dr. Cosentino has received personal compensation in the range of $500-$4,999 for serving as a Consultant for SAGE Pharmaceuticals.

Dupilumab but not cyclosporine treatment shifts the microbiome toward a healthy skin flora in patients with moderate-to-severe atopic dermatitis.

Atopic dermatitis (AD) patients display an altered skin microbiome which may not only be an indicator but also a driver of inflammation. We aimed to investigate associations among AD patients' skin microbiome, clinical data, and response to systemic therapy in patients of the TREATgermany registry. Skin swabs of 157 patients were profiled with 16S rRNA gene amplicon sequencing before and after 3 months of treatment with dupilumab or cyclosporine. For comparison, 16s microbiome data from 258 population-based healthy controls were used. Disease severity was assessed using established instruments such as the Eczema Area and Severity Index (EASI). We confirmed the previously shown correlation of Staphylococcus aureus abundance and bacterial alpha diversity with AD severity as measured by EASI. Therapy with Dupilumab shifted the bacterial community toward the pattern seen in healthy controls. The relative abundance of Staphylococci and in particular S. aureus significantly decreased on both lesional and non-lesional skin, whereas the abundance of Staphylococcus hominis increased. These changes were largely independent from the degree of clinical improvement and were not observed for cyclosporine. Systemic treatment with dupilumab but not cyclosporine tends to restore a healthy skin microbiome largely independent of the clinical response indicating potential effects of IL-4RA blockade on the microbiome.

Working memory heterogeneity from age 7 to 11 in children at familial high risk of schizophrenia or bipolar disorder– The Danish High Risk and Resilience Study

BackgroundDespite the genetic overlap between bipolar disorder and schizophrenia, working memory impairments are mainly found in children of parents with schizophrenia. However, working memory impairments are characterized by substantial heterogeneity, and it is unknown how this heterogeneity develops over time. We used a data-driven approach to assess working memory heterogeneity and longitudinal stability in children at familial high risk of schizophrenia (FHR-SZ) or bipolar disorder (FHR-BP). MethodsBased on the performances on four working memory tasks by 319 children (FHR-SZ, N = 202, FHR-BP, N = 118) measured at age 7 and 11, latent profile transition analysis was used to test for the presence of subgroups, and the stability of subgroup membership over time. Population-based controls (VIA 7, N = 200, VIA 11, N = 173) were included as a reference group. The working memory subgroups were compared based on caregiver- and teacher ratings of everyday working memory function, and dimensional psychopathology. ResultsA model with three subgroups characterized by different levels of working memory function (an impaired subgroup, a mixed subgroup, and an above average subgroup) best fitted the data. The impaired subgroup had the highest ratings of everyday working memory impairments and psychopathology. Overall, 98 % (N = 314) stayed in the same subgroup from age 7 to 11. ConclusionPersistent working memory impairments are present in a subset of children at FHR-SZ and FHR-BP throughout middle childhood. Attention should be given to these children, as working memory impairments influence daily life, and may serve as a vulnerability marker of transition to severe mental illness.

Abstract 1186: Contraception and ovarian cancer risk by tumor immune profiles

Abstract Introduction: An estimated 38 million US women currently use contraception, a critical component of women’s health. Yet, the impact of changing contraceptive types and patterns of use on ovarian cancer incidence is unclear and the biologic pathway through which contraception influences ovarian cancer risk is not well understood. Using multiplex immunofluorescence (mIF) technology, we evaluated how contraception influences the tumor immune microenvironment (e.g., T cells) to better understand the association of intrauterine device (IUD) and oral contraception (OC) use on ovarian cancer risk. Methods: We measured tumor immune profiles via mIF on tissue microarrays including tumor cores from 214 women with ovarian cancer (85% high grade serous) and 414 population-based controls frequency matched on age who participated in the New England Case Control Study. T cell types were defined by expression of CD3+ (total T cells), CD3+CD4+ (helper), CD3+CD8+ (cytotoxic), CD3+CD4+FoxP3+ (regulatory), CD3+CD4+CD69+ or CD3+CD8+CD69+ (recently activated), or CD3+Tim3+ or CD3+Lag3+(exhausted). The average immune cell density across 3 cores per tumor was used to categorize tumors as high or low abundance based on the median across all tumors. Contraception use was self-reported and included having ever used an IUD and/or OCs and duration of use. Polytomous logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for ovarian cancer defined by tumor immune cell abundance adjusted for age at diagnosis or interview, parity, and family history of breast or ovarian cancer in first degree relative. Results: Overall, ever use of IUD or OC was not differentially associated with ovarian cancer risk by T cell tumor immune profiles. However, for OC use of 5 years or longer, we observed a significant reduction in risk for low-abundance total T cell (ORlow=0.44, 95% CI 0.21-0.94), cytotoxic T cell (ORlow=0.44, 95% CI:0.21-0.94), regulatory T cell (ORlow=0.31, 95% CI: 0.14-0.68), and recently activated T cell (CD3+CD4+CD69+ ORlow=0.34, 95% CI: 0.17-0.68) tumors with significant trends with longer duration. There was no significant decrease in risk of tumors with high abundance of these T cell types, although statistically significant heterogeneity was only observed in the association for duration of OC use and risk by low and high abundance of recently activated helper T cells (CD3+CD4+CD69+, p-het=0.006). Conclusion: These results suggest that ever use of IUD and OCs are not associated with risk of ovarian tumors by immune phenotype, though risk by T cell abundance may vary with longer duration. Analyses are ongoing and will be expanded to include types and patterns of contraception, other immune markers, and additional studies. Citation Format: Jennifer Mongiovi, Ana Babic, Naoko Sasamoto, Mary Townsend, Allison Vitonis, Jonathan Hecht, Jose Conejo-Garcia, Brooke Fridley, Shelley Tworoger, Kathryn Terry. Contraception and ovarian cancer risk by tumor immune profiles [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 1186.