👤 Ryan Avery

Menopause may coincide with rising Lp(a) levels, a causal risk factor for atherosclerotic cardiovascular disease (ASCVD). Characterizing changes in Lp(a) across menopause may inform risk stratification and testing recommendations. . We examined changes in serum Lp(a) levels by menopausal status among women with Lp(a) measured at visits 1 and 2 in the UK Biobank. Lp(a) analyses were examined by menopausal status: those who underwent menopause (N=415), those who remained premenopausal (N=532), and those who remained postmenopausal (N=3,615) between visits. We examined the change in Lp(a) between visits stratified by visit 1 Lp(a) levels. The primary outcome was incident Lp(a) ≥125 nmol/L at visit 2, estimated using Poisson regression with adjustment for baseline age. Data were available for 4,562 women (mean age at visit 1 = 57±7 years; median Lp(a) at visit 1 = 22 (IQR: 47) nmol/L; median time between visits = 4 (IQR: 1) years). At visit 1, median Lp(a) was slightly higher in postmenopausal women (23 nmol/L) than premenopausal women (19 nmol/L). Overall, median changes in Lp(a) between visits 1 and 2 were modest. Among women with intermediate visit 1 Lp(a) levels (75-125 nmol/L), those who transitioned through menopause experienced a median increase of 34.9 (-6.7, 53.0) nmol/L between visits, an approximately fourfold greater increase than for women who remained pre- (7.9 nmol/L) or postmenopausal (8.0 nmol/L). Further, 56% of women with intermediate visit 1 Lp(a) levels who transitioned through menopause between visits had incident Lp(a) ≥125 nmol/L at visit 2, compared with 29% and 28% of women who remained pre- or postmenopausal, representing an age-adjusted risk ratio of 2.26 (95% CI: 1.31, 3.90). Relying on a single lifetime Lp(a) measurement may miss clinically relevant increases during menopause. Repeat testing in women as they age may improve identification of those at high risk for ASCVD. Show less

Mendelian randomization studies suggest a causal effect of lipoprotein(a) (Lp(a)) on atherosclerotic cardiovascular disease. Noncardiovascular effects (eg, diabetes risk) are inadequately investigated. In this noninterventional phenome-wide association study designed to better understand the potential causal role of Lp(a), direct causal phenotypic effects of exposure to Lp(a) were estimated. Also, the association between LPA null allele rs41272114 with type 2 diabetes was assessed, and ancestry-specific Lp(a) thresholds were determined. In the UK Biobank (n = 425,677 adults, 55% female), we studied 1,456 phenotypes spanning 18 classes using 4 ancestry-specific polygenic risk scores and false discovery rate multiple testing correction. Network deconvolution Mendelian randomization was leveraged to separate direct from indirect (ie, associations via mediating variables) causal phenotypic effects and account for confounding, reverse causation, and bidirectionality. Lp(a) was significantly associated with 80 phenotypes across 7 classes. Higher Lp(a) exposure had significant direct causal effects, independent of low-density lipoprotein cholesterol, on coronary artery disease (OR: 1.36; 95% CI: 1.21-1.54) and glycated hemoglobin (HbA1c; β = 0.099; 95% CI: 0.051-0.15) only. Very low Lp(a) exposure was not associated with type 2 diabetes (OR: 0.92; 95% CI: 0.64-1.31) or HbA1c (β = -0.016; 95% CI: -0.062 to 0.030). Among European and African ancestries, 86 (77th percentile) and 93 (59th percentile) nmol/L optimally discriminated myocardial infarction risk, respectively. Increasing Lp(a) exposure had direct, independent causal effects on coronary artery disease and HbA1c only; very low Lp(a) exposure is suggested to not be causally associated with type 2 diabetes. The optimal European and African ancestry threshold to stratify cardiovascular risk is comparable, and below 125/105 nmol/L in current U.S./European medical professional society guidelines. Show less

Little is known about the importance of blood lipids for risk of myocardial infarction (MI) in Chinese vs. European populations. We compared the associations with MI of apolioprotein B (ApoB) vs. low-density lipoprotein cholesterol (LDL-C) and remnant-cholesterol (remnant-C) vs. triglycerides in the China Kadoorie Biobank (CKB) and UK Biobank (UKB). Plasma levels of LDL-C, high-density lipoprotein-cholesterol (HDL-C), apolipoprotein B (ApoB), apolipoprotein A1 (ApoA1), non-HDL-C, remnant-C, LDL-C/ApoB, and HDL-C/ApoA1 ratios were measured in a nested case-control study of MI (948 cases, 6101 controls) in CKB and a prospective study (5344 cases in 279 989 participants) in UKB. Associations of lipids with MI were assessed using logistic regression in CKB and Cox regression in UKB after adjustment for confounders and correction for regression dilution. The mean levels of LDL-C were about 30% lower in CKB than in UKB [2.3 (0.6) vs. 3.7 (0.8) mmol/L], but mean levels of HDL-C were comparable [1.3 (0.3) vs. 1.5 (0.4) mmol/L], as were those for triglycerides [1.8 (1.1) vs. 1.7 (1.1) mmol/L]. While the rate ratios (RRs) of MI for 1 SD higher usual levels of LDL-C in Chinese were about half those in Europeans (1.27; 1.13-1.44 vs. 1.55; 1.49-1.61), the corresponding RRs for ApoB or non-HDL with MI were comparable between Chinese and Europeans. The findings reinforce current guidelines for primary prevention of atherosclerotic cardiovascular disease (ASCVD) in China that advocate initiation of statin treatment in individuals at high-risk of ASCVD rather than high levels of LDL-C. Show less

Integrated analyses of plasma proteomics and genetic data in prospective studies can help assess the causal relevance of proteins, improve risk prediction, and discover novel protein drug targets for type 2 diabetes (T2D). We measured plasma levels of 2,923 proteins using Olink Explore among ∼2,000 randomly selected participants from China Kadoorie Biobank (CKB) without prior diabetes at baseline. Cox regression assessed associations of individual protein with incident T2D (n = 92 cases). Proteomic-based risk models were developed with discrimination, calibration, reclassification assessed using area under the curve (AUC), calibration plots, and net reclassification index (NRI), respectively. Two-sample Mendelian randomization (MR) analyses using cis-protein quantitative trait loci identified in a genome-wide association study of CKB and UK Biobank for specific proteins were conducted to assess their causal relevance for T2D, along with colocalization analyses to examine shared causal variants between proteins and T2D. Overall, 33 proteins were significantly associated (false discovery rate <0.05) with risk of incident T2D, including IGFBP1, GHR, and amylase. The addition of these 33 proteins to a conventional risk prediction model improved AUC from 0.77 (0.73-0.82) to 0.88 (0.85-0.91) and NRI by 38%, with predicted risks well calibrated with observed risks. MR analyses provided support for the causal relevance for T2D of ENTR1, LPL, and PON3, with replication of ENTR1 and LPL in Europeans using different genetic instruments. Moreover, colocalization analyses showed strong evidence (pH4 > 0.6) of shared genetic variants of LPL and PON3 with T2D. Proteomic analyses in Chinese adults identified novel associations of multiple proteins with T2D with strong genetic evidence supporting their causal relevance and potential as novel drug targets for prevention and treatment of T2D. Show less

To date, at least 20 different amyloidogenic proteins have been documented. Growing evidence suggests that despite being part of the universal amyloid proteome, apolipoprotein A-IV can be amyloidogenic, accounting for less than 1% of cases. A 75-year-old woman was admitted for paroxysmal nocturnal dyspnoea and intermittent exertional shortness of breath and was found to be in acute heart failure. The patient underwent intravenous diuretic therapy and was discharged after decongestion. She then underwent a battery of outpatient tests to determine aetiology of her heart failure. Cardiac magnetic resonance imaging showed severe concentric left ventricular hypertrophy and diffuse late gadolinium enhancement, concerning for amyloidosis, but serologic evaluation for amyloidogenic light chain (AL) amyloidosis was negative. Tc 99m pyrophosphate (PYP) scan showed Grade 2 uptake at 1 h that was only moderately suggestive of transthyretin (TTR) amyloidosis. She ultimately received a right heart catheterization and endomyocardial biopsy, which showed apolipoprotein A-IV amyloid deposition within Congo red-positive areas of the endomyocardial specimen. The patient continues to report dyspnoea on exertion but has avoided additional heart failure admissions with intensification of her diuretic regimen. In this case, nuclear PYP scan to evaluate for TTR amyloidosis demonstrated focal PYP uptake, but endomyocardial biopsy demonstrated apolipoprotein A-IV deposition without evidence of TTR amyloidosis. Our case increases knowledge of this rare form of amyloidosis, suggests that it may result in false positive nuclear PYP results, and highlights the importance of its evaluation, particularly in circumstances in which investigations do not reveal definitive evidence of AL or TTR amyloidosis. Show less

Correct recognition, description, and classification of acetabular fractures is essential for efficient patient triage and treatment. Acetabular fractures may result from high-energy trauma or low-energy trauma in the elderly. The most widely used acetabular fracture classification system among radiologists and orthopedic surgeons is the system of Judet and Letournel, which includes five elementary (or elemental) and five associated fractures. The elementary fractures are anterior wall, posterior wall, anterior column, posterior column, and transverse. The associated fractures are all combinations or partial combinations of the elementary fractures and include transverse with posterior wall, T-shaped, associated both column, anterior column or wall with posterior hemitransverse, and posterior column with posterior wall. The most unique fracture is the associated both column fracture, which completely dissociates the acetabular articular surface from the sciatic buttress. Accurate categorization of acetabular fractures is challenging because of the complex three-dimensional (3D) anatomy of the pelvis, the rarity of certain acetabular fracture variants, and confusing nomenclature. Comparing a 3D image of the fractured acetabulum with a standard diagram containing the 10 Judet and Letournel categories of acetabular fracture and using a flowchart algorithm are effective ways of arriving at the correct fracture classification. Online supplemental material is available for this article. Show less

Disease of the teeth and their support structures is common and frequently seen at imaging of the head and neck. Recognition of dental disease by the interpreting radiologist has the potential to alter the course of patient care, such as when periapical disease is identified as the cause of sinusitis or pericoronitis is identified as the cause of deep neck infection. Furthermore, incidental recognition of carious lesions in both children and adults who are undergoing CT for other reasons may alert the patient and care team of the need for a dental consultation. In fact, most of the images of dental and periodontal conditions that are used in this article were obtained from CT studies that were performed to investigate other problems. Familiarity with the imaging appearance of common dental conditions, such as hyperdontia and hypodontia, tooth trauma, periodontal disease, caries, periapical disease, odontogenic sinusitis, and deep neck infections, allows the radiologist to render a timely, confident, and specific diagnosis of dental abnormalities, even when such findings are unexpected. Show less