Reference Cohort Research Articles

Effects of primary hyperparathyroidism on oral health. Alongitudinal register-based study.

To analyze the effects of primary hyperparathyroidism on oral health and to investigate if the effects are linked to severity of the disease. This prospective cohort study involved 6151 primary hyperparathyroidism patients registered in the Scandinavian Quality Registry of Thyroid, Parathyroid, and Adrenal surgery and the National Cancer Register after parathyroidectomy (exposure) during 2011-2017 (patient cohort) and 60,654 individuals without primary hyperparathyroidism (reference cohort), matched by age, gender, and county of resident at the date of parathyroidectomy. The outcomes were tooth extractions and periodontal interventions. The risk for the outcomes was assessed by Poisson regression models. After adjusting for covariates, the patient cohort had a higher incidence rate of tooth extraction during the two-year period after parathyroidectomy (IRR=1.15; 95% CI=1.01-1.31), but a lower incidence rate of periodontal interventions during the four- to six-year period after parathyroidectomy (IRR=0.88; 95% CI=0.79-0.99). Furthermore, patients with more severe primary hyperparathyroidism were more likely to have tooth extractions and periodontal interventions after parathyroidectomy. The risk of tooth extraction increased slightly during the first two years after parathyroidectomy. Thereafter, the oral health effects subsided. Pre-surgical serum ionized calcium levels and adenoma weight may indicate negative dental outcomes after parathyroidectomy.

Cut-offs for thyroid peroxidase and thyroglobulin antibodies in early pregnancy.

Thyroid disease in women of reproductive age is mainly of autoimmune origin, and thyroid peroxidase antibodies (TPO-Ab) as well as thyroglobulin antibodies (Tg-Ab) are key markers. Adding to this, much focus in pregnancy is on euthyroid women who are thyroid antibody positive. Evidence to substantiate the cut-offs for the definition of thyroid autoantibody positivity in early pregnant women is warranted. Stored serum samples from 14,030 Danish pregnant women were used for the measurement of TPO-Ab, Tg-Ab, TSH, and free thyroxine (ADVIA Centaur XPT, Siemens Healthineers). Among all women, a reference cohort of 10,905 individuals was identified for the establishment of antibody cut-offs. Percentile cut-offs for TPO-Ab and Tg-Ab were determined using regression on order statistics (the reference cohort). The established cut-offs were then applied (the full cohort), and frequencies of early pregnancy as well as later diagnosis of hypothyroidism were evaluated. The highest established cut-offs (95th, 97.5th, and 99th percentiles) were 59, 68, and 81 U/mL for TPO-Ab and 33, 41, and 52 U/mL for Tg-Ab. When the cut-offs were applied in the full cohort, 11.0, 10.2, and 9.7% were TPO-Ab positive, whereas 13.3, 12.3, and 11.2% were Tg-Ab positive. Antibody-positive women (TPO-Ab and/or Tg-Ab) had higher median TSH and were more likely to have hypothyroidism in early pregnancy and to be diagnosed with hypothyroidism during follow-up. This large study established and evaluated pregnancy-specific cut-offs for TPO-Ab and Tg-Ab. The findings are important regarding the classification of exposure in pregnancy and assessment of thyroid autoimmunity per se.

Transvaginal Mesh-related Complications and the Potential Role of Bacterial Colonization: An Exploratory Observational Study

This study aimed to investigate the potential role of transvaginal mesh bacterial colonization in the development of mesh-related complications (MRCs). An observational and exploratory study. Tertiary referral center (Amsterdam UMC, location AMC, Amsterdam, The Netherlands). PATIëNTS: 49 patients indicated for mesh removal and 20 women of whom vaginal tissue was retrieved during prolapse surgery as a reference cohort. collection of mesh-tissue complex (patient cohort) or vaginal tissue (reference cohort) MEASUREMENTS AND MAIN RESULTS: Homogenized samples were used for quantitative microbiological culture. Inflammation and fibrosis were semiquantitatively histologically scored; Gram staining and fluorescence in situ hybridization were used to detect bacteria and bacterial biofilms. Of the 49 patients, 44 samples (90%) were culture positive, with a higher diversity of species and more Gram-negative bacteria and polymicrobial cultures in the MRC cohort than the reference cohort, with mostly staphylococci, streptococci, Actinomyces spp., Cutibacterium acnes, and Escherichia coli. Patients with clinical signs of infection or exposure had the highest bacterial counts. Histology demonstrated moderate to severe inflammation in most samples. Gram staining showed bacteria in 57% of culture-positive samples, and in selected samples, fluorescence in situ hybridization illustrated a polymicrobial biofilm. In this study, we observed distinct differences in bacterial numbers and species between patients with MRCs and a reference cohort. Bacteria were observed at the mesh-tissue interface in a biofilm. These results strongly support the potential role of bacterial mesh colonization in the development of MRCs.

Does a closed reduction improve aesthetical and functional outcome after nasal fracture?

How closed reduction (CR) to repair a nasal fracture affects the patient's quality of life (QoL) has not been investigated. Here, we assessed QoL before and after CR using disease-specific questionnaires and compared the QoL scores of patients with nasal fractures with normative scores from a reference cohort. This was a prospective study of 96 patients with nasal fractures undergoing CR. Patients were interviewed about aesthetic, functional, and QoL issues before and after surgery using the Functional Rhinoplasty Outcome Inventory (FROI-17) and the Rhinoplasty Outcome Evaluation (ROE). Photographs of the nasal area were taken before and after surgery and reviewed. Data were compared with those from a reference cohort (n = 1000). Most fractures were type I (80.6%) and most were caused by sport-related accidents (36.5%). The ROE scores increased from 67.3 preoperatively to 73.4 postoperatively (p = 0.001). The FROI-17 also improved, indicating the overall effect of the nose on QoL (p = 0.002). Compared with the reference cohort, patients felt more affected by nasal symptoms before surgery (- 9.37, p = 0.02) than by more general aspects. ROE scores returned to normative values after surgery (p < 0.001). The postoperative cohort had lower scores for the FROI-17 item overall effects of the nose on QoL than the reference cohort did, although the nasal symptom score remained higher in patients than in reference controls. This study showed that CR can improve the aesthetical but not the functional outcome of the nose.

Societal economic burden and determinants of costs for atopic dermatitis

AbstractBackgroundAtopic dermatitis (AD) is a common inflammatory skin disease while the economic burden of AD by severity is not adequately understood.ObjectiveTo estimate the societal economic burden and to identify cost determinants of AD.MethodsIn this population‐based, controlled cohort study in Sweden, patients with AD were identified through diagnosis codes in primary or secondary care or by dispensed medications using administrative healthcare registers. A reference cohort without AD was randomly selected from the general population. Healthcare costs (primary/secondary care visits and dispensed medication) and indirect costs (care for sick children and long‐term sick leave for adults) were calculated annually. AD patients were stratified by age (paediatric [age &lt; 12], adolescent [12 ≤ age &lt; 18] or adult [age ≥ 18]), and severity (mild‐to‐moderate [M2M] or severe AD) and matched to the reference cohort.ResultsCompared with controls, the annual mean per‐patient direct healthcare costs in the first year following diagnosis were €941 and €1259 higher in paediatric patients with M2M and severe AD, respectively. In the first year following diagnosis, the mean indirect cost for care of sick children was €69 and €78 higher per patient in M2M and severe AD, respectively. In adolescents with M2M and severe AD, direct healthcare costs were €816 and €1260 higher, respectively. In adults, healthcare costs were €1583 and €2963 higher in patients with M2M and severe AD, respectively and indirect costs were €148 and €263 higher compared with controls. Management of comorbid medical conditions was an important driver of incremental healthcare costs. Total incremental societal economic burden for AD was €351 and €96 million higher in patients with M2M and severe AD, respectively, compared to controls.ConclusionAD is associated with a significant societal economic burden primarily driven by the cost burden of M2M AD due to the high prevalence of this population. Regardless of severity level, management of non‐AD comorbidities is a major driver of total costs.

Quality-of-life outcomes in older patients with early-stage rectal cancer receiving organ-preserving treatment with hypofractionated short-course radiotherapy followed by transanal endoscopic microsurgery (TREC): non-randomised registry of patients unsuitable for total mesorectal excision

Older patients with early-stage rectal cancer are under-represented in clinical trials and, therefore, little high-quality data are available to guide treatment in this patient population. The TREC trial was a randomised, open-label feasibility study conducted at 21 centres across the UK that compared organ preservation through short-course radiotherapy (SCRT; 25 Gy in five fractions) plus transanal endoscopic microsurgery (TEM) with standard total mesorectal excision in adults with stage T1-2 rectal adenocarcinoma (maximum diameter ≤30 mm) and no lymph node involvement or metastasis. TREC incorporated a non-randomised registry offering organ preservation to patients who were considered unsuitable for total mesorectal excision by the local colorectal cancer multidisciplinary team. Organ preservation was achieved in 56 (92%) of 61 non-randomised registry patients with local recurrence-free survival of 91% (95% CI 84-99) at 3 years. Here, we report acute and long-term patient-reported outcomes from this non-randomised registry group. Patients considered by the local colorectal cancer multidisciplinary team to be at high risk of complications from total mesorectal excision on the basis of frailty, comorbidities, and older age were included in a non-randomised registry to receive organ-preserving treatment. These patients were invited to complete questionnaires on patient-reported outcomes (the European Organisation for Research and Treatment of Cancer Quality of Life [EORTC-QLQ] questionnaire core module [QLQ-C30] and colorectal cancer module [QLQ-CR29], the Colorectal Functional Outcome [COREFO] questionnaire, and EuroQol-5 Dimensions-3 Level [EQ-5D-3L]) at baseline and at months 3, 6, 12, 24, and 36 postoperatively. To aid interpretation, data from patients in the non-randomised registry were compared with data from those patients in the TREC trial who had been randomly assigned to organ-preserving therapy, and an additional reference cohort of aged-matched controls from the UK general population. This study is registered with the ISRCTN registry, ISRCTN14422743, and is closed. Between July 21, 2011, and July 15, 2015, 88 patients were enrolled onto the TREC study to undergo organ preservation, of whom 27 (31%) were randomly allocated to organ-preserving therapy and 61 (69%) were added to the non-randomised registry for organ-preserving therapy. Non-randomised patients were older than randomised patients (median age 74 years [IQR 67-80] vs 65 years [61-71]). Organ-preserving treatment was well tolerated among patients in the non-randomised registry, with mild worsening of fatigue; quality of life; physical, social, and role functioning; and bowel function 3 months postoperatively compared with baseline values. By 6-12 months, most scores had returned to baseline values, and were indistinguishable from data from the reference cohort. Only mild symptoms of faecal incontinence and urgency, equivalent to less than one episode per week, persisted at 36 months among patients in both groups. The SCRT and TEM organ-preservation approach was well tolerated in older and frailer patients, showed good rates of organ preservation, and was associated with low rates of acute and long-term toxicity, with minimal effects on quality of life and functional status. Our findings support the adoption of this approach for patients considered to be at high risk from radical surgery. Cancer Research UK.

The LSC17 Score Correlates with the ELN 2022 Classification of AML and Is an Independent Predictor of Detectable Measurable Residual Disease after Induction Chemotherapy

Introduction: An emerging trend for targeted treatment in AML has led to increased treatment options, however variable outcomes remain even with a targeted approach suggesting novel approaches are needed. To date, risk stratification of AML patients has relied on cytogenetic and genomic data as there has been no CLIA-certified biomarker to assess how leukemia stem cells (LSC) contribute to disease resistance at a clinical level. The LSC17 score predicts risk based on stemness features in AML patients at diagnosis and is strongly associated with survival after standard induction therapy (Ng, Nature 2016). A NanoString clinical assay for the LSC17 score has recently been validated in a CLIA-certified laboratory (Ng, Blood Advances 2022) and can provide a rapid result within 72 hours of diagnosis for incorporation into upfront treatment decisions. Recent updates in AML have led to an improved risk stratification at cytogenetic and genomic levels (ELN 2022). Here we carried out a new analysis to assess the value of the LSC17 score as an independent predictor of outcomes in AML patients in the context of the updated ELN 2022 classification. Methods: Data from recent validation and prospective feasibility studies were analyzed. Only patients that received induction chemotherapy were included in the analysis. Patients with a confirmed diagnosis of acute promyelocytic leukemia were excluded from analysis. In our studies the LSC17 score was measured in parallel with standard prognostic markers including cytogenetics, molecular studies and targeted sequencing using a standard myeloid panel. Patients’ ELN status was updated using the 2022 classification scheme and was correlated with treatment response and survival. Results: 190 patients were included in our analysis. LSC17 scores ranged from 0 to 1.25, and were classified as high or low according to the median score of 0.51 from our reference cohort (Ng, Blood Advances 2022). Of the 190 patients, 84 had a low LSC17 score and 106 had a high LSC17 score. Patients received induction chemotherapy with three different protocols: standard 3+7 (n = 141), Flag-IDA (n =40) and CPX-351 (n = 9). We first considered the impact of the ELN 2022 classification and how it altered prognostic categorization in our cohort. Using ELN 2017 criteria, 48 (27%), 51 (29%), and 77 (44%) of patients had favorable, intermediate and adverse risk disease, respectively. 14 patients were not classifiable as cytogenetic testing failed. Using the ELN 2022 hierarchical classification, patients were categorized into low (n=44), intermediate (n = 53) and high (n = 93) risk groups. Changes in prognostic classification were most evident in the intermediate risk category where 11 patients were upgraded to high-risk disease due to the presence of myelodysplasia-related disease mutations. When the LSC17 score was considered as a continuous variable, the median LSC17 score was statistically different between the three ELN 2022 risk groups (0.24 [range 0-0.8] vs 0.48 [range 0.04-1.13] vs 0.73 [range 0.14-1.25] for low, intermediate and high-risk, respectively; P<0.001, Figure 1). Measurable residual disease (RD) is associated with poor clinical outcomes. Prediction of RD can identify patients who may benefit from alternative treatment approaches. We therefore assessed the ability of the LSC17 score to predict RD positivity after induction chemo in the context of ELN 2022. In our cohort, 141 patients (74%) had RD testing performed after induction. In univariate analysis, RD positivity was associated with both ELN 2022 high-risk disease (P=0.001, OR 12.7) and a high LSC17 score (P<0.001, OR = 7.7). In multivariate analysis incorporating both variables, both ELN high risk (P=0.02, OR 5.56, 95% CI 1.35 -22.85) and high LSC17 score (P=0.007, OR 3.98, 95% CI 1.44 -11.01) retained independent prognostic value. Conclusion: The LSC17 score measured by the clinical NanoString-based assay correlates with the updated ELN 2022 risk classification and importantly is an independent predictor of RD positivity irrespective of mutational status. Measurement of the LSC17 score at diagnosis will enable identification of patients with high probability of treatment refractoriness. This study highlights the potential role of the LSC17 score in future risk-adapted clinical studies of novel induction candidates. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Disease burden in primary sclerosing cholangitis in the Netherlands: A long-term follow-up study.

Primary sclerosing cholangitis (PSC) is a progressive, cholestatic liver disease which greatly impacts the lives of individuals. Burden of disease due to shortened life expectancy and impaired quality of life is ill-described. The aim of this study was to assess long-term disease burden in a large population-based registry with regard to survival, clinical course, quality adjusted life years (QALYs), medical consumption and work productivity loss. All PSC patients living in a geographically defined area covering ~50% of the Netherlands were included, together with patients from the three liver transplant centres. Survival was estimated by competing risk analysis. Proportional shortfall of QALYs during disease course was measured relative to a matched reference cohort using validated questionnaires. Work productivity loss and medical consumption were evaluated over time. A total of 1208 patients were included with a median follow-up of 11.2year. Median liver transplant-free survival was 21.0 years. Proportional shortfall of QALYs increased to 48% >25 years after diagnosis. Patients had on average 12.4 hospital contact days among which 3.17 admission days per year, annual medical costs were €12 169 and mean work productivity loss was 25%. Our data quantify for the first time disease burden in terms of QALYs lost, clinical events, medical consumption, costs as well as work productivity loss, and show that all these are substantial and increase over time.

PATH-33. “GENETIC AND EPIGENETIC PROFILING IDENTIFIES TWO DISTINCT CLASSES OF SPINAL MENINGIOMAS”

Abstract BACKGROUND Spinal meningiomas account for 1.2-12 % of all meningiomas and 25-45 % of all spinal tumours. 20 % of intracranial, but only 4.6 % of spinal meningiomas recur requiring additional treatment. Whereas the classification of intracranial meningiomas has evolved considerably in recent years and uses genetic and epigenetic parameters, the classification of spinal meningiomas is based solely on histopathological findings. By embedding epi-/genetic features, the prognosis of intracranial meningiomas could be significantly improved, which is still lacking for spinal meningiomas. In our work, we integrated genetic and epigenetic parameters into the classification of spinal meningiomas. METHODS We performed epi-/genetic profiling of 50 spinal meningiomas. 497 intracranial meningiomas served as a reference cohort. Copy number variations (CNV) were inferred from the methylation data. Principal component (PCA) and t-SNE analysis were conducted. Clinical and histopathological parameters (location, size, recurrence, WHO°, pathological subtype) were correlated with methylation signatures using the DKFZ brain tumour classifier. RESULTS The methylation signature of spinal meningiomas matched to that of intracranial meningiomas (50/50), although meningioma subgroup assignment was achieved in only 13/50 cases. PCA and t-SNE analysis showed that most spinal meningiomas separate from cranial meningiomas and form two distinct clusters. Cluster 1 matched the methylation class ben-2, while cases in cluster 2 were heterogenous and had a low MSC score. Cases of cluster 1 were located in the upper spine, are more common in males and had an AKT1E17K mutation. NF2 mutations were found mainly in the second cluster, in line with a chr.22 q loss. Interestingly 4 tumors did not associate with the two spinal meningioma clusters and had a particular higher recurrence rate. CONCLUSION Genetic and epigenetic profiling of spinal meningiomas identifies two distinct classes of spinal meningiomas, which may allow an improved prognosis that could lead to a better guidance for adjuvant therapy.

In RA patients without prevalent CVD, incident CVD is mainly associated with traditional risk factors: A 20-year follow-up in the CARRÉ cohort study

ObjectivesTo extend our investigation of cardiovascular diseases (CVD) in rheumatoid arthritis (RA) patients to a follow up of more than 20 years, with a special focus on patients without prevalent CVD. MethodsThe CARRÉ study is an ongoing prospective cohort study on CV endpoints in RA patients. Results were compared to those of a reference cohort (n = 2484) enriched for type 2 diabetes mellitus (DM). Hazard ratios (HR) for RA and DM patients compared to non-RA/-DM controls were calculated with cox proportional hazard models, and adjusted for baseline SCORE1 (estimated 10-year CVD mortality risk based on CV risk factors). Results238 RA patients, 117 DM patients and 1282 controls, without prevalent CVD at baseline were included. Analysis of events in these patients shows that after adjustment, no relevant ‘RA-specific’ risk remains (HR 1.16; 95%CI 0.88 – 1.53), whereas a ‘DM-specific’ risk is retained (1.73; 1.24 – 2.42). In contrast, adjusted analyses of all cases confirm the presence of an ‘RA-specific’ risk (1.50; 1.19 – 1.89). ConclusionsIn RA patients without prevalent CVD the increased CVD risk is mainly attributable to increased presence of traditional risk factors. After adjustment for these factors, an increased risk attributable to RA only was thus preferentially seen in the patients with prevalent CVD at baseline. As RA treatment has improved, this data suggests that the ‘RA-specific’ effect of inflammation is preferentially seen in patients with prevalent CVD. We suggest that with modern (early) treatment of RA, most of the current increased CVD risk is mediated through traditional risk factors.

Abnormal preoperative platelet count may predict postoperative complications following shoulder arthroplasty.

The purpose of this study is to investigate the association between preoperative platelet counts and postoperative complication rates within 30 days of total shoulder arthroplasty (TSA). The American College of Surgeons National Surgical Quality Improvement database was queried for all patients who underwent TSA between 2015 and 2019. The study population was then divided into 5 groups based on their preoperative platelet count: <100k (moderate-to-severe thrombocytopenia), 100-150k (mild thrombocytopenia), 150-200k (low-normal preoperative platelet count), 200-450k (normal, reference cohort), and >450k (thrombocytosis). Postoperative complications within 30 days of the TSA were collected. Multivariate logistic regression analysis was conducted to investigate the relationship between preoperative platelet counts and postoperative complications. A total of 19,721 patients undergoing TSA between 2015 and 2019 were included in this study. One hundred fifty-five patients (0.8%) had moderate-to-severe thrombocytopenia, 982 (5.0%) had mild thrombocytopenia, 3945 (20.0%) had a low-normal preoperative platelet count, 14,386 (72.9%) had a normal preoperative platelet count, and 253 (1.3%) had thrombocytosis. An increasing rate of overall complications was observed as the severity of thrombocytopenia progressed from low-normal (6.4%) to mild thrombocytopenia (10.2%) and to moderate-to-severe thrombocytopenia (18.7%). The overall complication rate of the thrombocytosis cohort was 14.6%. In comparison to normal platelet count, low-normal thrombocytopenia, mild thrombocytopenia, moderate-to-severe thrombocytopenia, and thrombocytosis were identified by multivariate analysis as significant predictors of overall complications (odds ratios [ORs] of 1.12, 2.15, 2.43, 2.71, respectively), postoperative anemia requiring transfusion (ORs of 1.63, 3.45, 5.97, 4.21, respectively), and minor complications (ORs of 1.39, 2.64, 3.40, 3.34, respectively). Minor complications include progressive renal insufficiency, urinary tract infection, transfusions within 72 hours after surgery, pneumonia, and superficial incisional surgical site infection. Increasing severity of thrombocytopenia correlated with higher overall postoperative complication rates following TSA. Interestingly, patients with thrombocytosis had the highest overall postoperative complication rates among all cohorts included in this study. Platelet counts are often the reflection of other comorbidities and a good indicator of patient's general health status. Long-term optimization of abnormal platelet counts may potentially reduce surgical complications.

OR14-2 Age of Onset of Obesity and Childhood BMI Trajectories in Rare Genetic Obesity Disorders

Abstract Introduction Early-onset obesity is a cardinal feature of rare genetic obesity disorders. According to the Endocrine Society guideline, genetic screening is indicated in selected cases with age of onset (AoO) of severe obesity (grade ≥2) &amp;lt;5 years. However, this cut-off is not validated. Aims To present the detailed BMI characteristics of children and adolescents with rare genetic obesity disorders; to evaluate whether the following growth chart characteristics can aid in assessing which children should be screened for genetic obesity disorders: AoO of obesity, AoO of severe obesity, BMI standard deviation scores (SDS) at yearly age intervals. Methods In this prospective observational study, children with non-syndromic and syndromic genetic obesity disorders treated at our tertiary obesity center were included. Growth measurements from birth onwards were collected. Children with obesity from a population-based cohort study with follow-up until age 10 years were included as an unselected reference cohort. Diagnostic performance (sensitivity [sens], specificity [spec], positive likelihood ratio [LR+], area-under-the-curve [AUC]) for AoO of obesity and severe obesity and for BMI-SDS at yearly age intervals was calculated. Results We included 64 children with genetic obesity disorders (32 non-syndromic, 32 syndromic) and 298 control children with obesity. At intake, median age of children with genetic obesity was 10.5 years (IQR 7.0–14.7) and mean BMI-SDS +3.1 ± 1.1. Median AoO of obesity was 1.2 years (IQR 0.6–3.7) in non-syndromic genetic obesity, 2.1 years (IQR 0.9–4.2) in syndromic genetic obesity, and 3.8 years (IQR 2.3–6.2) in the control population. For non-syndromic genetic obesity, optimal cut-off value for AoO of obesity was ≤1.5 years: sens 0.60, spec 0.88, LR+ 5.22, AUC 0.79 (p&amp;lt;0.001). For syndromic genetic obesity, optimal cut-off was ≤3.0 years: sens 0.68, spec 0.68, LR+ 2.06, AUC 0.67 (p=0.001). AoO of severe obesity showed worse diagnostic performance than AoO of obesity in both non-syndromic (AUC 0.58, p=0.20) and syndromic genetic obesity (AUC 0.58, p=0.21). Moreover, when the guideline cut-off &amp;lt;5 years was used, AoO of severe obesity showed a negative diagnostic performance (non-syndromic genetic obesity: sens 0.76, spec 0.13, LR+ 0.88; syndromic genetic obesity: sens 0.85, spec 0.14, LR+ 0.98). BMI-SDS showed good diagnostic performance for non-syndromic genetic obesity across the age intervals (AUCs 0.79-0.89, all P&amp;lt;0.001) but not for syndromic genetic obesity (AUCs 0.54-0.71, P-values ranging from &amp;lt;0.001-0.50). Conclusion This study shows that growth charts characteristics such as BMI-SDS and AoO of obesity (grade 1), but not AoO of severe obesity (grade ≥2), could be useful to distinguish between children with genetic obesity disorders and children with obesity from a population-based cohort study. However, all investigated growth charts characteristics showed misclassification, especially in syndromic genetic obesity, indicating that additional clinical features should be present to warrant genetic testing in these children. Presentation: Sunday, June 12, 2022 11:15 a.m. - 11:30 a.m.

Association of Vaginal Progesterone Treatment With Prevention of Recurrent Preterm Birth

Preterm birth (PTB) is the leading cause of infant morbidity and mortality worldwide. It has been suggested that vaginal progesterone (VP) treatment may reduce the recurrence of PTB. To evaluate the association of VP treatment with prevention of recurrent PTB among patients with a singleton pregnancy. This prospective, observational cohort study, set in a public health care system for inner-city pregnant patients, enrolled patients with prior spontaneous PTB (gestational age, ≤35 weeks) receiving VP from May 15, 2017, to May 7, 2019. Patients who delivered between 1998 and 2011 served as a referent cohort matched 3:1 for obesity, race and ethnicity, and individual specific preterm birth history. Statistical analysis was performed from August 19, 2021, to September 2, 2022. Patients received 90 mg of vaginal progesterone, 8%, nightly, initiated between 16 weeks and 0 days and 20 weeks and 6 days of pregnancy until 36 weeks and 6 days of pregnancy or delivery. The primary outcome was overall rate of recurrent PTB at 35 weeks or less of patients given VP compared with the 3:1 matched untreated historical controls. Secondary outcomes included assessment of PTB according to adherence (≥80% completing scheduled doses), duration of pregnancy relative to index gestational age, progesterone blood levels, and outcomes for those who declined VP. A total of 417 patients (mean [SD] age, 30.4 [5.9] years; 64 Black patients [15.3%]; 272 [65.2%] with a body mass index of ≥30) received VP and were matched with 1251 controls (mean [SD] age, 28.8 [5.7] years; 192 Black patients [15.3%]; 816 [65.2%] with a body mass index of ≥30). The overall rate of recurrent PTB was 24.0% (100 of 417; 95% CI, 20.0%-28.4%) for the VP cohort compared with 16.8% (1394 of 8278) expected in the matched historical controls. Adherence was not associated with lower rates of recurrent PTB compared with nonadherence (odds ratio, 0.87 [95% CI, 0.51-1.41]). The mean difference between historical matched controls and those using VP was 0.2 weeks (95% CI, -1.4 to 1.0 weeks) without improvement in the interval of recurrent PTB after the implementation of VP (P = .73). Progesterone blood levels for patients who were adherent compared with those who were nonadherent were not significantly different at either 24 or 32 weeks (24 weeks: 99 ng/mL [95% CI, 85-121 ng/mL] vs 104 ng/mL [95% CI, 89-125 ng/mL]; P = .16; 32 weeks: 200 ng/mL [95% CI, 171-242 ng/mL] vs 196 ng/mL [95% CI, 155-271 ng/mL]; P = .69). This cohort study of patients with a current singleton pregnancy suggests that VP was not associated with a reduction in recurrent PTB.

Association of Premenopausal Bilateral Oophorectomy With Parkinsonism and Parkinson Disease

The association of premenopausal bilateral oophorectomy with parkinsonism and Parkinson disease (PD) remains controversial. To assess whether women who underwent premenopausal bilateral oophorectomy were at increased risk of parkinsonism and PD and whether the associations varied by age at oophorectomy and by receipt of estrogen replacement therapy. This cohort study used data from a combination of 2 independent cohort studies, the Mayo Clinic Cohort Study of Oophorectomy and Aging 1 and 2, which were based on the Rochester Epidemiology Project medical records-linkage system. A population-based sample of 5499 women from Olmsted County, Minnesota, were included; of those, 2750 women underwent bilateral oophorectomy for a benign indication before spontaneous menopause between January 1, 1950, and December 31, 2007 (oophorectomy cohort), and 2749 age-matched women who did not undergo bilateral oophorectomy were randomly sampled from the general population (reference cohort). Data were analyzed from March 1 to April 30, 2022. The date of oophorectomy was considered the index date for both groups. Medical record documentation of bilateral oophorectomy abstracted from a medical records-linkage system (Rochester Epidemiology Project). Incidence and risk of parkinsonism or PD, with diagnoses confirmed by in-person examination or medical record review. Among 5499 participants (median [IQR] age, 45.0 [40.0-48.0] years; 5312 [96.6%] White), 2750 women (2679 White [97.4%]) underwent bilateral oophorectomy at a median age of 45.0 years (IQR, 40.0-48.0 years), and 2749 women (2633 White [95.8%]) with a median age of 45.0 years (IQR, 40.0-48.0 years) at the index date were included in the reference cohort. Bilateral oophorectomy was associated with an increased risk of parkinsonism overall (hazard ratio [HR], 1.59; 95% CI, 1.02-2.46) and in women younger than 43 years at oophorectomy (HR, 7.67; 95% CI, 1.77-33.27). There was a pattern of increasing risk with younger age at the time of oophorectomy using 4 age strata (≥50 years: HR, 1.43 [95% CI, 0.50-4.15]; 46-49 years: HR, 1.55 [95% CI, 0.79-3.07]; 40-45 years: HR, 1.36 [95% CI, 0.64-2.89]; <40 years: HR, 8.82 [95% CI, 1.08-72.00]; P = .02 for trend). The number needed to harm was 53 women overall and 27 women younger than 43 years at the time of oophorectomy. Bilateral oophorectomy was also associated with an increased risk of PD in women younger than 43 years at oophorectomy (HR, 5.00; 95% CI, 1.10-22.70), with a number needed to harm of 48 women. Among women who underwent oophorectomy at 45 years and younger, the risk was lower in women who received estrogen after the procedure and through age 50 years compared with women who did not. For parkinsonism, the HRs were 1.72 (95% CI, 0.54-5.53) vs 2.05 (95% CI, 0.80-5.23); for PD, the HRs were 1.53 (95% CI, 0.29-8.23) vs 2.75 (95% CI, 0.84-9.04). However, the differences were not significant. In this study, premenopausal women who underwent bilateral oophorectomy before age 43 years had an increased risk of parkinsonism and PD compared with women who did not undergo bilateral oophorectomy. These findings suggest that a reduction in the practice of prophylactic bilateral oophorectomy in premenopausal women at average risk of ovarian cancer may have substantial benefit for reducing the risk of parkinsonism and PD.

SGLT2 inhibitor therapy for transthyretin amyloid cardiomyopathy: early tolerance and clinical response to dapagliflozin.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve clinical outcomes in heart failure patients with reduced and preserved left ventricular ejection fraction (LVEF), but have not yet been investigated in transthyretin amyloid cardiomyopathy (ATTR-CM). This study aimed to evaluate tolerability, clinical outcomes, and changes in NT-proBNP levels and glomerular filtration rate (GFR) in ATTR-CM patients treated with dapagliflozin. Patients with stable, tafamidis-treated ATTR-CM were retrospectively evaluated at the initiation of dapagliflozin and 3months thereafter. Tafamidis-treated ATTR-CM patients without SGLT2i served as a reference cohort. Overall, SLGT2i therapy was initiated in 34 patients. Seventeen patients with stable disease on tafamidis, who were subsequently started on dapagliflozin, were included in the analysis. Patients selected for SGLT2i presented with signs of advanced disease, evidenced by higher Gillmore disease stage (stage ≥2: 53% vs. 27.5%; P=0.041), baseline median NT-proBNP [median (IQR) 2668pg/mL (1314-3451) vs. 1424 (810-2059); P=0.038] and loop diuretic demand (76.5% vs. 45% of patients; P=0.044), and lower LVEF (46.6±12.9 vs. 53.7±8.7%; P=0.019) and GFR (51.8±16.5 vs. 68.5±18.6mL/min; P=0.037) compared with the reference cohort. At 3-month follow-up, a numerical decrease in NT-proBNP levels was observed in 13/17 (76.5%) patients in the dapagliflozin (-190pg/mL, IQR: -1,028-71, P=0.557) and 27/40 (67.5%) of patients in the control cohort (-115pg/mL, IQR: -357-105, P=0.551). Other disease parameters remained stable and no adverse events occurred. In tafamidis-treated ATTR-CM patients, initiation of dapagliflozin was well tolerated. The efficacy of SGLT2i therapy in patients with ATTR-CM needs to be studied in randomized controlled trials.

Identification of Early Onset Dementia in Population-Based Health Administrative Data: A Validation Study Using Primary Care Electronic Medical Records.

Early onset dementia (EOD) occurs when symptoms of dementia begin between 45 to 64 years of age. We developed and validated health administrative data algorithms for EOD and compared demographic characteristics and presence of comorbid conditions amongst adults with EOD, late onset dementia (LOD) and adults with no dementia in Ontario, Canada. Patients aged 45 to 64 years identified as having EOD in their primary care electronic medical records had their records linked to provincial health administrative data. We compared several combinations of physician's claims, hospitalizations, emergency department visits and prescriptions. Age-standardized incidence and prevalence rates of EOD were estimated from 1996 to 2016. The prevalence of EOD for adults aged 45 to 64 years in our primary care reference cohort was 0.12%. An algorithm of ≥1 hospitalization or ≥3 physician claims at least 30 days apart in a two-year period or ≥1 dementia medication had a sensitivity of 72.9% (64.5-81.3), specificity of 99.7% (99.7-99.8), positive predictive value (PPV) of 23.7% (19.1-28.3), and negative predictive value of 100.0%. Multivariate logistic regression found adults with EOD had increased odds ratios for several health conditions compared to LOD and no dementia populations. From 1996 to 2016, the age-adjusted incidence rate increased slightly (0.055 to 0.061 per 100 population) and the age-adjusted prevalence rate increased three-fold (0.11 to 0.32 per 100 population). While we developed a health administrative data algorithm for EOD with a reasonable sensitivity, its low PPV limits its ability to be used for population surveillance.

Socioeconomic outcomes beyond 30 years of age in a cohort born with very low birth weight.

As survival of infants born prematurely has increased dramatically, questions on long-term consequences have emerged. Our aim was to investigate long-term effects of very low birth weight on socioeconomic outcomes. One hundred and fifty very low birth weight infants (VLBW) born from 1980 to 1982 at Rigshospitalet, Denmark, who had previously been followed up at age 2, 4 and 18 years, were compared to cohorts of low birth weight, normal birth weight (NBW) and a national population-based reference cohort. From the Danish national registers we obtained data regarding educational level, financial independence and living arrangements. In addition, we used the previously published results from the three cohorts. The VLBW cohort had lower intelligence quotient and higher risk of significant school difficulties evaluated at age 4 and 18 years. When compared to the NBW cohort, at 30-36 years of age the VLBW cohort tended to have lower educational level, OR 1.7, 95% CI 0.8-3.9, were not financially independent OR 1.5, 95% CI 0.6-3.7, lived alone OR 2.0, 95% CI 1.0-3.8 and had higher rates of the combination of all three outcomes, OR 3.2, 95% CI 0.7-15.8. We found trends towards poor socioeconomic outcomes in young adults born with VLBW. The relative disadvantages appeared smaller than that in childhood.

Reference Interval for Serum L-Homoarginine Determined with Enzyme-Linked Immunosorbent Assay in the Population-Based Study of Health in Pomerania.

Low levels of the endogenous amino acid L-homoarginine are a risk factor for cardiovascular morbidity and mortality. For individual risk prediction, commercially available test systems are mandatory. This study aims at formulating sex- and age-specific reference intervals of serum L-homoarginine determined with an ELISA. We determined reference intervals for serum L-homoarginine stratified by age and sex in a sample of 1285 healthy participants of the Study of Health in Pomerania (SHIP)-TREND cohort after exclusion of participants with cardiovascular diseases, diabetes mellitus, hypertension, metabolic syndrome, elevated liver enzymes, chronic kidney disease stages III or IV, or body mass index &gt;25 kg/m2. Serum L-homoarginine was determined applying a commercially available ELISA. The reference cohort included 836 women (median age 41, 25th and 75th percentiles are 32 and 50 years) and 449 men (median age 38, 25th, and 75th percentiles are 30 and 49 years). The median serum concentration of L-homoarginine was 1.93 (25th 1.49; 75th 2.60) µmol/L in women and 2.02 (25th 1.63; 75th 2.61) µmol/L in men (P = 0.04). The reference intervals (2.5th to 97.5th percentile) were 0.89-5.29 µmol/L for women and 1.09-3.76 µmol/L for men. The L-homoarginine serum concentration declined over age decades in both sexes and a notable interaction with sex hormone intake in women was observed. The novelty of our study is that we determined reference intervals specific for the L-isomer being lower than those previously reported for homoarginine in SHIP and thus might be helpful in identifying individuals suitable for oral L-homoarginine supplementation.

Association between carbon monoxide poisoning and adrenal insufficiency: a nationwide cohort study

Carbon monoxide poisoning may damage the brain and adrenal glands, but it is unclear whether it is associated with adrenal insufficiency. We identified all COP patients diagnosed between 1999 and 2012 in Taiwan using the Nationwide Poisoning Database and selected a reference cohort (participants without COP) from the same database by exact matching of age and index date at a 1:2 ratio. Participants with a history of adrenal insufficiency or steroid use of more than 14 days were excluded. We followed up participants until 2013 and compared the risk of developing adrenal insufficiency between the two cohorts. The 21,842 COP patients had a higher risk for adrenal insufficiency than the 43,684 reference participants (adjusted hazard ratio [AHR] = 2.5; 95% confidence interval [CI]: 1.8–3.5) after adjustment for sex and underlying comorbidities (liver disease, thyroid disease, mental disorder). The risk continued to elevate even after 1 year (AHR = 2.1; 95% CI: 1.4–3.4). The COP patients who had acute respiratory failure had an even higher risk for adrenal insufficiency than those without acute respiratory failure, which may indicate a dose–response relationship. Stratified analyses showed that female patients had an elevated risk (AHR = 3.5; 95% CI: 2.1–6.0), but not male patients. Younger patients (< 50 years) had higher risks, and the AHR reached statistical significance in the age groups 20–34 (AHR = 5.5; 95% CI: 1.5–20.6) and 35–49 (AHR = 4.9; 95% CI: 2.3–10.6) years old. The risk for developing adrenal insufficiency elevated after COP, especially in female and younger patients. Carbon monoxide is the most common gaseous agent causing acute intoxication worldwide. Results of the current study call for monitoring adrenal function of patients with COP.

Lower incidence of hospital-treated infections in infants under 3 months of age vaccinated with BCG

BackgroundLive vaccines potentially have non-specific effects that protect against other infections than those the vaccines are targeted against. The national vaccination program (NVP) in Finland was changed on September 1st, 2006: before BCG vaccine was given to all newborn babies and afterwards to babies in risk groups only. We used this natural experiment to study the non-specific effects of BCG in the frame of NVP using before-after design. MethodsWe compared the incidence of several outcomes obtained from Finnish health registers between children born between July 1st, 2004, and June 30th, 2006 (BCG-eligible) and an age- and season-matched reference cohort born between July 1st, 2007, and June 30th, 2009 (BCG-non-eligible) using Poisson regression. These cohorts were restricted to full-term children whose parents were born in Finland. Follow-up began at birth and lasted 3 months, which is the scheduled age for DTaP-IPV-Hib vaccination, and from 4 months until first birthday. The outcomes included all infections, pneumonia and injuries as a negative control outcome. ResultsThe incidence rate ratio (IRR) of the BCG-eligible cohort (N = 93,658) compared to BCG-non-eligible cohort (N = 94,712) for hospital-diagnosed infections was 0.89 (95 %Cl 0.86–0.93) for the 3-month follow-up. The decrease was mainly caused by respiratory infections. In 4–12 months follow-up the BCG-eligible had slightly more infections than BCG-non-eligible children (IRR 1.03, 1.01–1.06). ConclusionsBCG vaccination was associated with a lower incidence of all hospital-diagnosed infections during the first three months of life. The difference cannot be attributed to lung tuberculosis, since only few paediatric cases occurred in Finland during 2000s. The disappearance of non-specific effect after administration of an inactivated vaccine is compatible with previous studies.