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Abstract We developed an open source, extensible Python‐based framework, that we call the Versatile Modeling Of Deformation (VMOD), for forward and inverse modeling of crustal deformation sources. VMOD abstracts from specific source model implementations, data types and inversion methods. We implement the most common geodetic source models which can be combined to model and analyze multi‐source deformation. VMOD supports Global Navigation Satellite System (GNSS), InSAR, electronic distance measurement, Leveling and tilt data. To infer source characteristics from observations, VMOD implements non‐linear least squares and Markov Chain Monte‐Carlo Bayesian inversions, including joint inversions using different sources of data. VMOD's structure allows for easy integration of new geodetic models, data types, and inversion strategies. We benchmark the forward models against other published results and the inversion approaches against other implementations. We apply VMOD to analyze deformation at Unimak Island, Alaska, observed with continuous and campaign GNSS, and ascending and descending InSAR time series generated from Sentinel‐1 satellite radar acquisitions. These data show an inflation pattern at Westdahl volcano and subsidence at Fisher Caldera. We use VMOD to test a range of source models by jointly inverting the GNSS and InSAR data sets. Our final model simultaneously constrains the parameters of two sources. Our results reveal a depressurizing spheroid under Fisher Caldera ∼4–6 km deep, contracting at a rate of ∼2–3 Mm3/yr, and a pressurizing spherical source underneath Westdahl volcano ∼6–8 km deep, inflating at ∼5 Mm3/yr. This and past applications of VMOD to volcanic unrest benefit from an extensible framework which supports jointly inversions of data sets for parameters of easily composable multi‐source models.

This paper analyzes the social drive, from the shared foundation of behavioral psychology, ethology, and attachment theory. It explores how the social drive has been considered a secondary or acquired drive and identifies the original advocates for this perspective, while outlining their prerequisites for primary drives. This provides a framework for empirical investigation which include 1) having a physiological component, 2) survival value for the species, 3) not relying on pairing with other primary reinforcers, and 4) displaying covariation with behavior based on satiation and deprivation. The paper gradually moves from older studies to modern ones, demonstrating that the social drive fulfills all criteria, by utilizing older empirical studies on isolation, bad rearing, neonatal social reinforceability, as well as modern research on social deprivation/satiation and loneliness. The paper concludes by discussing the implications of this reclassification on existing psychological theories, and its potential to influence future psychotherapeutic treatments., Competing Interests: Declaration of competing interest none., (Copyright © 2025 The Author. Published by Elsevier B.V. All rights reserved.)

Importance: Transthyretin tetramer destabilization is the rate-limiting step in the development of transthyretin cardiac amyloidosis, an underrecognized contributor to mortality in older adults., Objective: To test the hypothesis that transthyretin tetramer destabilization is associated with all-cause and cardiovascular mortality in the general population., Design, Setting, and Participants: In this cohort study including individuals aged 20 to 80 years, genetic data were analyzed from 2 similar prospective studies of the Danish general population, the Copenhagen City Heart Study (CCHS) and the Copenhagen General Population Study (CGPS). Observational data from a subsample of the same studies where transthyretin was measured consecutively were also analyzed. In both studies, individuals were followed up from the examination date (1991-1994 in CCHS and 2003-2015 in CGPS) until death or the end of follow-up in December 2018. Data were analyzed from November 1, 2023, to August 15, 2024., Exposures: Missense variants in TTR associated with increasing transthyretin tetramer destabilization in primary genetic analyses, and plasma transthyretin level in secondary observational analyses., Main Outcomes and Measures: All-cause and cardiovascular mortality identified from the national Danish Civil Registration System and the national Danish Register of Causes of Death., Results: A total of 102 204 individuals (median [IQR] age, 57 [47-66] years; 56 445 [55%] female) were included. Median follow-up was 10 years (range, <1-27 years). In genetic analyses, p.T139M, a transthyretin tetramer stabilizing variant that is more stable than noncarriers' tetramer stability, was used as the reference. For noncarriers who have intermediate tetramer stability and for heterozygotes for amyloidogenic variants (p.V142I, p.H110N, and p.D119N) who have the lowest tetramer stability, respective hazard ratios (HRs) were 1.37 (95% CI, 1.06-1.77) and 1.65 (95% CI, 0.95-2.88) for all-cause mortality (P for trend = .01), and 1.63 (95% CI, 0.92-2.89) and 2.23 (95% CI, 0.78-6.34) for cardiovascular mortality (P for trend = .06). Furthermore, compared with p.T139M, plasma transthyretin decreased stepwise by TTR genotype: -18% for noncarriers and -29% for heterozygotes for amyloidogenic variants (p.V142I, p.H110N, p.D119N; P for trend < .001). Therefore, genetically determined, increasingly lower plasma transthyretin could be considered a surrogate marker for transthyretin tetramer destabilization. Observationally, among 19 619 individuals, noncarriers with plasma transthyretin concentrations less than 20 mg/dL vs 20 to 40 mg/dL had HRs of 1.12 (95% CI, 1.02-1.23) for all-cause mortality and 1.16 (95% CI, 0.97-1.39) for cardiovascular mortality., Conclusions and Relevance: Transthyretin tetramer destabilization was associated with all-cause and cardiovascular mortality in the Danish general population. These findings may suggest a need for large-scale assays to measure transthyretin destabilization for detection of transthyretin amyloidosis before clinical manifestations emerge, since early treatment improves the prognosis.

Streptococci are well-known opportunistic bacterial abortifacients in mares. Colonization of the pregnant uterus is considered to happen after transcervical migration of bacteria from the lower genital tract mucosa. Streptococcus ovis is a pathogen mainly associated with inflammatory lesions in sheep. This species has not been reported in association with disease in horses. In the present case, S. ovis was isolated in monoculture from the lung of an 8-months-old equine fetus and was associated with development of acute suppurative bronchopneumonia, umbilical cord cellulitis and placentitis in the cervical star region of the allantochorion. The mare had been in a pasture together with sheep. One week prior to abortion, a double-guarded uterine swab had been inserted into the cervical canal by a veterinarian, who was unaware of the mare being pregnant. This probably damaged the cervical mucus plug thus allowing S. ovis bacteria to pass the cervical canal and colonize the placenta., Competing Interests: Declaration of competing interest None of the authors has any financial or personal relationships that could inappropriately influence or bias the content of the paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Aims: We tested the association of polygenic risk scores (PRS) for low-density lipoprotein cholesterol (LDL-C) and coronary artery disease (CAD) with LDL-C and risk of ischemic heart disease (IHD) in the Danish general population., Methods: We included a total of 21,485 individuals from the Copenhagen General Population Study and Copenhagen City Heart Study. For everyone, LDL-PRS and CAD-PRS were calculated, each based on >400,000 variants. We also genotyped four rare variants in LDLR or APOB known to cause familial hypercholesterolemia (FH)., Results: Heterozygous carriers of FH-causing variants in APOB or LDLR had a mean LDL-C of 5.40 and 6.09 mmol/L, respectively, and an odds ratio for IHD of 2.27 (95 % CI 1.43-3.51) when compared to non-carriers. The LDL-PRS explained 13.8 % of the total variation in LDL-C in the cohort. Individuals in the lowest and highest 1 % of LDL-PRS had a mean LDL-C of 2.49 and 4.75 mmol/L, respectively. Compared to those in the middle 20-80 %, those in the lowest and highest 1 % of LDL-PRS had odds ratios for IHD of 0.58 (95 % CI, 0.38-0.88) and 1.83 (95 % CI, 1.33-2.53). The corresponding odds ratios for CAD-PRS were 0.61 (95 % CI, 0.41-0.92) and 2.06 (95 % CI, 1.49-2.85)., Conclusions: The top 1 % of LDL-PRS and CAD-PRS conferred effects on LDL-C and risk of IHD comparable to those seen for carriers of rare FH-causing variants in APOB or LDLR. These results highlight the potential value of implementing such PRS clinically., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Professor Gerhard Sand (1861-1921) was the first professor of veterinary obstetrics at the Royal Veterinary and Agricultural University, Copenhagen, Denmark. He began teaching the theory and practice of obstetrics to veterinary students in 1887 and spent the following years until his death in 1921 developing the veterinary obstetrics teaching program. During this period, veterinary obstetrics was established as an independent discipline at the Royal Veterinary and Agricultural University. Professor Sand's teaching had a major impact on the field of veterinary obstetrics in Scandinavia. He was devoted to teaching veterinary obstetrics and produced a number of obstetrical illustrations, some of which showed different causes of dystocia, mainly fetal malpresentation in cattle and horses. Professor Sand created the illustrations with the intention of publishing a handbook of obstetrics, but due to illness and an early death, this work was never completed. This compilation of historical artworks of dystocia in cattle and horses includes some of these illustrations and is published to honour Professor Sand, with the intention of making his illustrations widely available for the teaching of veterinary obstetrics., (© 2024. The Author(s).)

Equine pregnancy failure can occur throughout gestation with etiologies varying by region. In Europe, umbilical cord torsion (UCT) has been reported to account for up to 52% of abortions and stillbirths. Little is known about what causes excessive twisting of the umbilical cord (UC), and up till now, only the length of the UC has been identified as a risk factor for UCT. The aim of the present study was to determine the association of potential maternal and fetal risk factors with UCT and umbilical cord length (UCL). A retrospective cohort study was performed on aborted or prematurely delivered stillborn fetuses submitted for necropsy, and a follow-up questionnaire survey was sent to mare owners to obtain additional anamnestic data. In total 72 cases were included in the study. Multivariable regression analyses were performed to evaluate the risk factors (mare size, period of gestation, gestational length, parity, previous abortion, UCL, maternal age at abortion and fetal sex) association with UCT and UCL, and Wilcoxon rank sum test tested pairwise differences in UCL for the risk factors mare size, period of gestation and cause of abortion. Abortion caused by UCT (UCTA) was diagnosed in 37 cases, and these had shorter gestational length (8.1 ± 0.3 months) compared to fetuses lost to other causes (8.9 ± 0.2 months) (p = 0.002). UCTAs accounted for the highest prevalence of abortions in the mid gestational period (113-227 days) (14/21, 67%) compared to the late period (228-314 days) (22/50, 44%) (p = 0.05). The cause of abortion was associated with period of gestation (p = 0.009) and UCL (p = 0.002), and fetuses aborted as a consequence of UCT had longer UCs (98.84 ± 5.14 cm) compared to abortions due to other causes (67.2 ± 4.9 cm). Mares in the mid period of gestation had 7.9 times the odds of UCTA compared to the late period (CI: 1.93, 32.2), and UCL was associated with increased odds of UCTA (OR: 1.05, CI: 1.02, 1.07). UCL was associated with mare size (p = 0.012), period of gestation (p = 0.002) and cause of abortion (p = 0.001). In conclusion, UCTA was significantly associated with UCL and gestational length. The prevalence of UCTA was not influenced by mare size, but pony fetuses from UCTAs had significantly shorter UCs compared to horse fetuses. UCs longer than 54 cm may predispose ponies for UCTA. No other maternal or fetal risk factors were found to be associated with the cause of abortion., Competing Interests: Declaration of competing interest None., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Equine endometrial degeneration is diagnosed by microscopy of an endometrial biopsy but it is uncertain if findings in a single biopsy represent the state of the entire endometrium. Previous studies have compared samples from multiple sites but conclusions are inconsistent. Further clarification is therefore needed. In this study, presence and characteristics of endometrial degeneration were compared in two full thickness specimens from the ventral base of both uterine horns, obtained post mortem from cyclic mares (n = 82). Hematoxylin and eosin-stained sections were blinded evaluated for periglandular fibrosis, glandular nests, dilated glands, glandular dilation, excessive lymphatic vessels, and lymphatic lacunae. Each section was also assigned to a modified Kenney and Doig categorization. Statistical analysis included multiple logistic regression models for fraction of mares with disagreement in the modified Kenney and Doig category and fraction of mares with disagreement for each parameter, multiple generalized linear regression models for fraction of parameters with disagreement, and equivalence tests for agreement of a cumulative score of degenerative parameters. Possible effect of age, mare type and estrous cycle stage were included in the analyses. For the Kenney and Doig categorization, 49% of the mares had good agreement, 46% had moderate agreement and 5% had poor agreement between the two biopsies. Disagreement in the Kenney and Doig categorization between the two biopsies increased with age (OR = 1.1, P = 0.009). Disagreement within each parameter ranged from 10% of mares (glandular nests), to 31% (periglandular fibroblasts) and 37% (lymphatic lacunae). Disagreement for changes in endometrial glands increased with age (OR = 1.15-1.16, P < 0.040). Several mares (33%) had disagreement in at least two parameters, and the number of parameters with disagreement increased with age (HR = 1.04, P = 0.010). When tested for equivalence, the cumulative scores for paired endometrial samples did not differ for mares younger than 18 years (P = 0.011). In conclusion, the degenerative changes were not uniformly distributed, revealed by a disagreement between paired endometrial samples for individual parameters and for the Kenney and Doig categorization, which increased with age. This suggests that conclusions based on a single biopsy, particularly in mares over 17 years of age, should be interpreted with caution, and evaluation of two biopsies should be considered., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Extraosseous plasmacytoma (EOP) is a rare plasma cell neoplasm that tends to convert to plasma cell myeloma (PCM) in about 11% to 35% of cases. It has a predilection for the upper respiratory tract, prototypically affecting the nasal cavity and paranasal sinuses. Contemporary first-line treatment is radiotherapy, with more recent studies showing an added benefit of combining radiation with surgery. In this cohort study, we aimed to examine clinical presentation, treatment, and prognosis for all patients nationwide from 1980 through 2017. Furthermore, we determined the size and extension of tumors, investigating the rate at which minimally invasive surgery would have been possible., Methods: Patients were found in the national pathology registry, and all biopsies were collected for pathology review by a hematopathologist. We performed survival statistics for overall survival (OS), progression-free survival (PFS), and the cumulative incidence of conversion to PCM., Results: Twenty-three patients were included. The median age was 65, and patients were primarily men (78%). Tumors were located in either the nasal cavity (57%), maxillary sinus (39%), or sphenoid sinus (4%). In most cases, the tumor was <5 cm (65%) without extension to adjacent structures (60%). The national incidence was 0.02/100,000 person-years, the median symptom duration until diagnosis was 5 months, and none of the patients presented with contiguous spread to regional lymph nodes. Stand-alone radiotherapy was the predominant treatment (61%). In the entire cohort, one patient died from the initial disease, and six patients died from either relapse of EOP or PCM. The 5-year OS, PFS, and conversion rate to PCM were 78%, 56%, and 23%, respectively., Conclusion: SN-EOP responds well to radiotherapy, but relapse and conversion to PCM were not uncommon and entailed a poor prognosis. Most tumors were endoscopically resectable and non-invasive, making the majority of tumors suitable for surgery as an addition to radiation.

Genetic variants in ABCA1 are associated with higher concentrations of high-density lipoprotein (HDL) cholesterol. Higher HDL cholesterol concentrations are observationally and genetically associated with higher risk of age-related macular degeneration (AMD). However, whether amino acid-changing genetic variants in ABCA1 associated with high HDL cholesterol concentrations confer a higher risk of AMD in the general population is currently unknown. We tested this hypothesis. The study included 80,972 individuals (1,370 AMD cases) from the Copenhagen General Population Study (CGPS) and 9,584 individuals (142 AMD cases) from the Copenhagen City Heart Study (CCHS) with 10 to 18 years of follow-up. We created an HDL cholesterol weighted allele score based on amino acid-changing ABCA1 variants with a minor allele frequency above 0.001 and divided it into tertiles. The study included 55% women. Mean age was 58 years. The ABCA1 allele score for the third versus the first tertile was associated with HRs (95% confidence intervals (CIs)) of 1.30 (1.14-1.49) for all-cause AMD, 1.26 (1.06-1.50) for nonneovascular AMD, and 1.31 (1.12-1.53) for neovascular AMD in a multivariable adjusted model. On a continuous scale, higher concentrations of genetically determined HDL cholesterol were associated with higher risk of all-cause AMD, nonneovascular AMD, and neovascular AMD in an age- and sex adjusted model and in a multivariable adjusted model. In conclusion, amino acid-changing genetic variants in ABCA1 associated with higher HDL cholesterol concentrations were also associated with higher risk of AMD, suggesting a role for ABCA1 in AMD pathogenesis., (© 2023. The Author(s).)

Compared to Asian and Latin American populations, sinonasal NK- or T-cell lymphoma is rare in Europe. All patients with sinonasal NK- or T-cell lymphoma in Denmark from 1980 to 2017 were validated histologically, and the disease behavior and demographics were extracted from medical records and national registries. Prognostic factors associated with mortality were determined using survival statistics. We included 56 patients: 40 extranodal NK/T-cell lymphoma (nasal type) (ENKTCL) and 16 peripheral T-cell lymphoma (not otherwise specified) (PTCL). The median age was 66, and most patients were male (72%). The ENKTCL and PTCL 5-year overall survival was 48% and 50%, respectively; progression-free survival was 38% for both. With ENKTCL, stage and performance status increased mortality significantly (HR = 8.6; p  < 0.001 and HR = 4.23; p  = 0.04). In conclusion, disseminated disease had a dismal outcome and the onset of ENKTCL in this ethnically homogeneous European cohort was about a decade later than reported in Asian populations.

Alzheimer's disease is the most common form of dementia, and the prodromal phases of Alzheimer's disease can last for decades. Vascular dementia is the second most common form of dementia and is distinguished from Alzheimer's disease by evidence of previous stroke or hemorrhage and current cerebrovascular disease. A compiled group of vascular-related dementias (vascular dementia and unspecified dementia) is often referred to as non-Alzheimer dementia. Recent evidence indicates that preventing dementia by lifestyle interventions early in life with a focus on reducing cardiovascular risk factors is a promising strategy for reducing future risk. Approximately 40% of dementia cases is estimated to be preventable by targeting modifiable, primarily cardiovascular risk factors. The aim of this review is to describe the association between risk factors for atherosclerotic cardiovascular disease and the risk of Alzheimer's disease and non-Alzheimer dementia by providing an overview of the current evidence and to shed light on possible shared pathogenic pathways between dementia and cardiovascular disease. The included risk factors are body mass index (BMI); plasma triglyceride-, high-density lipoprotein (HDL) cholesterol-, low-density lipoprotein (LDL) cholesterol-, and total cholesterol concentrations; hypertension; diabetes; non-alcoholic fatty liver disease (NAFLD); physical inactivity; smoking; diet; the gut microbiome; and genetics. Furthermore, we aim to disentangle the difference between associations of risk factors in midlife as compared with in late life.

Lymphomas of the nasal cavity and paranasal sinuses (NPS) are rare. Knowledge on sinonasal B-cell lymphoma (SNBCL) primarily comes from case series or single-center studies on small cohorts. We sought to determine the subtype distribution, clinical characteristics, disease behavior, and prognosis on a nationwide scale, with an emphasis on prognostic factors for the most common sinonasal lymphoma, primary sinonasal diffuse large B-cell lymphoma (PSDLBCL). We collated all data from medical records and national databases on patients registered with SNBCL from 1980 through 2018 in the national pathology registry and collected all tissue samples for validation of diagnosis. We included 205 patients and found 10 different subtypes of lymphoma. Diffuse large B-cell lymphoma (DLBCL) was the predominant subtype (80%). The incidence of SNBCL was 0.14/100,000 person-years. The five-year progression-free survival (PFS) and overall survival rates for PSDLBCL were 50% and 56%, respectively. For PSDLBCL, Rituximab showed a statistically significant effect (Hazard Ratio 0.22, p < 0.001), whereas consolidative radiotherapy combined with immunochemotherapy was of limited value (PFS, p = 0.93). When treatment failure occurred, DLBCL showed a distinct pattern of recurrence/dissemination to the NPS, skin, breast, central nervous system (CNS), and/or testis. Collectively, DLBCL comprised a clear majority of SNBCLs, although nine other subtypes were represented. Data showed that immunochemotherapy increased survival for PSDLBCL and that the addition of radiotherapy did not benefit patients. Furthermore, treatment failure for sinonasal DLBCL showed a possible common pathogenesis with primary extranodal lymphomas of specific locations (e.g., CNS, skin, breast, and testis)., (© 2022 The Authors. Hematological Oncology published by John Wiley & Sons Ltd.)

The present article reports a study conducted to develop and validate a Danish translation of the Purpose in Life test-Short Form (PIL-SF) and examine age effects on this eudemonic measure. The study examined the reliability, unidimensionality, and construct validity of the Danish PIL-SF using a large and representative sample (N = 4,849). The results indicated that the Danish PIL-SF is a reliable and valid measure of meaning and purpose in life, positively associated with but distinct from hedonic well-being. The high degree of similarity between the measurement properties of the Danish PIL-SF, as compared with the English-language PIL-SF, supports the validity of the Danish translation. Furthermore, the unidimensional structure of the Danish measure replicates the structure of the English-language PIL-SF. Given its large and representative sample, the present study provides the current best estimate of a normative population value for the PIL-SF. Also, the present study is the first to our knowledge to explore potential relationships between age and the PIL-SF, and a small positive effect of age on the Danish PIL-SF was found. Limitations and suggestions for further research are discussed., (© 2021 Scandinavian Psychological Associations and John Wiley & Sons Ltd.)

Background: Loss of pregnancy in mares can have many different causes, including both infectious and non-infectious conditions. Extrapolation of findings from other studies is often uncertain as the significance of each cause varies across regions. Causes of pregnancy loss in mares have never been thoroughly studied in Denmark, so a prospective cross-sectional cohort study targeting the entire Danish population of pregnant mares was performed over a period of 13 months to obtain knowledge of the significance of individual causes. Fifty aborted or prematurely delivered stillborn fetuses were submitted for necropsy and examined by a panel of diagnostic laboratory methods. Results: Overall, a cause of fetal loss was established for 72% of the examined cases. Most cases (62%) were lost due to a non-infectious cause, of which obstruction of the feto-placental blood circulation due to severe torsion of the umbilical cord was most prevalent. Pregnancy loss due to a variety of opportunistic bacteria, including bacteria not previously associated with abortion in mares, accounted for 12%, while equid alphaherpesvirus (EHV) type 1 was the cause of pregnancy loss in 8% of the cases. EHV type 4 and Chlamydiaceae species were identified in some cases, but not regarded as the cause of fetal loss. Conclusion: Umbilical cord torsion was found to be the most prevalent cause of fetal loss in Danish mares, while infectious causes such as EHV type 1 and streptococci only accounted for a minor proportion of the losses. The study highlights the need for defined criteria for establishing an abortion diagnosis in mares, particularly in relation to EHV types 1 and 4., Competing Interests: E-MK is employed by Laboklin GmbH & Co., which is a company offering diagnostic tests. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Agerholm, Klas, Damborg, Borel, Pedersen and Christoffersen.)

Purpose of Review: Current methods to assess genetic risk of familial hypercholesterolemia and coronary artery disease (CAD) focus on testing monogenic mutations in well known genes. Here we review recent developments in polygenic risk scores (PRSs) for LDL cholesterol and for CAD, and how they may add to current risk prediction algorithms., Recent Findings: PRSs can identify 10-20 times as many individuals at high polygenic risk compared with monogenic mutations, and PRSs can modulate the effect of a monogenic variant on risk. Current risk factor prediction tools for prevention of CAD incompletely capture polygenic susceptibility, and PRSs may identify subgroups of patients who are likely to benefit more from lipid-lowering therapy. Finally, PRSs can be quantified already at birth, long before other risk factors used to predict CAD, and before clinical manifestations of disease., Summary: PRSs for CAD may soon be incorporated into clinical practice. Therefore, there is an urgent need to establish both analytical and clinical reporting standards for PRSs, and for validating scores in different ethnicities. Thresholds for intervention need to be established for PRSs and integrated into established risk scores. Training programs are needed for clinical staff to learn to communicate polygenic risk in a comprehensive way to the patient., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Importance: Several lines of evidence support low plasma transthyretin concentration as an in vivo biomarker of transthyretin tetramer instability, a prerequisite for the development of both wild-type transthyretin cardiac amyloidosis (ATTRwt) and hereditary transthyretin cardiac amyloidosis (ATTRm). Both ATTRm and ATTRwt cardiac amyloidosis may manifest as heart failure (HF). However, whether low plasma transthyretin concentration confers increased risk of incident HF in the general population is unknown., Objective: To evaluate whether low plasma transthyretin concentration is associated with incident HF in the general population., Design, Setting, and Participants: This study included data from 2 similar prospective cohort studies of the Danish general population, the Copenhagen General Population Study (CGPS; n = 9582) and the Copenhagen City Heart Study (CCHS; n = 7385). Using these data, first, whether low concentration of plasma transthyretin was associated with increased risk of incident HF was tested. Second, whether genetic variants in TTR associated with increasing tetramer instability were associated with lower transthyretin concentration and with higher risk of HF was tested. Data were collected from November 2003 to March 2017 in the CGPS and from November 1991 to June 1994 in the CCHS; participants from both studies were observed for survival time end points until March 2017. Data were analyzed from March to June 2019., Exposures: Transthyretin concentration at or below the 5th percentile, between the 5th and 95th percentile (reference), and greater than the 95th percentile; genetic variants in TTR., Main Outcome and Measure: Incident HF identified using the Danish National Patient Registry., Results: Of 9582 individuals in the CGPS, 5077 (53.0%) were women, and the median (interquartile range [IQR]) age was 56 (47-65) years. Of 7385 individuals in the CCHS, 4452 (60.3%) were women, and the median (IQR) age was 59 (46-70) years. During a median (IQR) follow-up of 12.6 (12.3-12.9) years and 21.7 (11.6-23.8) years, 441 individuals (4.6%) in the CGPS and 1122 individuals (15.2%) in the CCHS, respectively, developed HF. Baseline plasma transthyretin concentrations at or below the 5th percentile were associated with incident HF (CGPS: hazard ratio [HR], 1.6; 95% CI, 1.1-2.4; CCHS: HR, 1.4; 95% CI, 1.1-1.7). Risk of HF was highest in men with low transthyretin levels. Compared with p.T139M, a transthyretin-stabilizing variant, TTR genotype was associated with stepwise lower transthyretin concentrations for wild-type TTR (-16.5%), p.G26S (-18.1%), and heterozygotes for other variants (p.V142I, p.H110N, and p.D119N; -30.8%) (P for trend <.001). The corresponding HRs for incident HF were 1.14 (95% CI, 0.57-2.28), 1.29 (95% CI, 0.64-2.61), and 2.04 (95% CI, 0.54-7.67), respectively (P for trend = .04)., Conclusions and Relevance: In this study, lower plasma and genetically determined transthyretin concentrations were associated with a higher risk of incident HF, suggesting a potential mechanistic association between low transthyretin concentration as a marker of tetramer instability and incident HF in the general population.