Impact of duodenal-jejunal bypass liner (DJBL) on NAFLD in patients with obesity and type 2 diabetes mellitus.

OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) represents an excessively rising entity of chronic liver disease and is a leading cause of mortality among patients with metabolic syndrome. The duodenal-jejunal bypass liner (DJBL) is a minimally invasive endoscopic treatment option for patients with obesity and type 2 diabetes (T2DM). Although beneficial effects of DJBL therapy on body weight reduction and glycemic control have been described, the effects of DJBL implantation on NAFLD is unknown. The aim of this study was to to evaluate the effects of DJBL implantation for 6 to 9 months on biochemical and clinical biomarkers of NAFLD in a large cohort of patients. METHODS: The effect of DJBL treatment on biochemical and clinical parameters of NAFLD were assessed in a study cohort of 71 patients with obesity and T2DM. DJBL was implanted for 9 to 12 months and patients were regularly monitored during the implantation period and for a follow-up period of 6 months after explantation. RESULTS: DJBL therapy was associated with a significant decrease in fatty liver index during time of implantation (explantation versus implantation: 93.38 versus 98.22, P < 0.001). Moreover, DJBL implantation was associated with decreases of alanine aminotransferase (29.03 versus 42.29 U/L, P < 0.0001) and cytokeratin-18 fragments (CK18 MF30; 190.6 versus 276 U/L, P < 0.0001), that further remained stable during 6 months after explantation. NAFLD fibrosis and aspartate aminotransferase-to-platelet ratio index (APRI) scores decreased significantly during implantation (-0.83 versus 0.19, P < 0.001, 0.26 versus 0.36, P < 0.0001, respectively). CONCLUSIONS: To our knowledge, this is the first study to demonstrate significant effects of DJBL treatment on biochemical and clinical markers of NAFLD activity. Significant effects of DJBL treatment on NAFLD fibrosis and APRI score further suggests protective effects of DJBL on liver-related morbidity and mortality in patients with obesity and T2DM.

Screening for hypophosphatasia: does biochemistry lead the way?

OBJECTIVES: Patients with childhood hypophosphatasia (HPP) often have unspecific symptoms. It was our aim to identify patients with mild forms of HPP by laboratory data screening for decreased alkaline phosphatase (AP) within a pediatric population. METHODS: We conducted a retrospective hospital-based data screening for AP activity below the following limits: Girls: ≤12 years: <125 U/L; >12 years: <50 U/L Boys: ≤14 years: <125 U/L; >14 years: <70 U/L. Screening positive patients with otherwise unexplained hypophosphatasemia were invited for further diagnostics: Re-test of AP activity, pyridoxal 5'-phosphate (PLP) in hemolyzed whole blood, phosphoethanolamine (PEA) in serum and urine, and inorganic pyrophosphate in urine. Sequencing of the ALPL gene was performed in patients with clinical and/or laboratory abnormalities suspicious for HPP. RESULTS: We assessed a total of 14,913 samples of 6,731 patients and identified 393 screening-positive patients. The majority of patients were excluded due to known underlying diseases causing AP depression. Of the 30 patients who participated in the study, three had a decrease in AP activity in combination with an increase in PLP and PEA. A heterozygous ALPL mutation was detected in each of them: One patient with a short stature was diagnosed with childhood-HPP and started with enzyme replacement therapy. The remaining two are considered as mutation carriers without osseous manifestation of the disease. CONCLUSIONS: A diagnostic algorithm based on decreased AP is able to identify patients with ALPL mutation after exclusion of the differential diagnoses of hypophosphatasemia and with additional evidence of increased AP substrates.

[CME Sonography 101: Ultrasound of the Musculoskeletal System - Update 2021]. / CME-Sonografie 101: Ultraschall am Bewegungsapparat ­ Update 2021 CME- Fragen.

CME Sonography 101: Ultrasound of the Musculoskeletal System - Update 2021 Abstract. Ultrasound technologies in medicine (and in many other areas of life) continuously undergo enormous technological advances. There is increasing automation in medicine, and this is also true for diagnostic imaging. This article describes the current state of the art in musculoskeletal ultrasound and takes a look into the near future.

[CME Sonography 101/Answers: Ultrasound of the Musculoskeletal System - Update 2021]. / CME-Sonografie 101/Antworten: Ultraschall am Bewegungsapparat ­ Update 2021.

CME Sonography 101/Answers: Ultrasound of the Musculoskeletal System - Update 2021 Abstract. Ultrasound technologies in medicine (and in many other areas of life) continuously undergo enormous technological advances. There is increasing automation in medicine, and this is also true for diagnostic imaging. This article describes the current state of the art in musculoskeletal ultrasound and takes a look into the near future.

RheumaTool, a novel clinical decision support system for the diagnosis of rheumatic diseases, and its first validation in a retrospective chart analysis.

AIMS: RheumaTool is a clinical decision support system designed to support the diagnostic process in rheumatology by presenting a differential diagnosis list after the input of clinical information. The objective of this study was to evaluate the performance of RheumaTool in detecting the correct diagnosis in referrals to a rheumatology clinic. METHODS: In this retrospective chart analysis, data were gathered from patients with musculoskeletal complaints and an uncertain diagnosis who were referred to a Swiss tertiary rheumatology outpatient clinic. Data were entered into RheumaTool in a standardised fashion, while the principal diagnoses in the medical reports were blinded. RheumaTool’s output was compared to the correct diagnoses, established either by widely accepted diagnostic criteria or through the expert consensus of independent rheumatologists. Diagnostic precision, the primary endpoint, was defined as the proportion of correctly diagnosed cases among all cases. RESULTS: One hundred and sixty cases with 46 different diseases were included in this analysis. RheumaTool correctly diagnosed 40% (95% confidence interval 32.4–48.1) of all cases. In 63.8% (95% confidence interval 55.7–71.1), the correct diagnosis was present in a differential diagnosis list consisting of a median of two diagnoses. CONCLUSION: In this first validation, RheumaTool provides a useful list of differential diagnoses. However, there is not sufficient diagnostic reliability for unfiltered data entry, especially in patients with multiple concomitant musculoskeletal disorders. This must be taken into account when using RheumaTool.

Breath acetone change during aerobic exercise is moderated by cardiorespiratory fitness.

Exhaled breath acetone (BrAce) was investigated during and after submaximal aerobic exercise as a volatile biomarker for metabolic responsiveness in high and lower-fit individuals in a prospective cohort pilot-study. Twenty healthy adults (19-39 years) with different levels of cardiorespiratory fitness (VO2peak), determined by spiroergometry, were recruited. BrAce was repeatedly measured by proton-transfer-reaction time-of-flight mass spectrometry (PTR-TOF-MS) during 40-55 min submaximal cycling exercise and a post-exercise period of 180 min. Activity of ketone and fat metabolism during and after exercise were assessed by indirect calorimetric calculation of fat oxidation rate and by measurement of venous ß-hydroxybutyrate (ßHB). Maximum BrAce ratios were significantly higher during exercise in the high-fit individuals compared to the lower-fit group (t-test; p= 0.03). Multivariate regression showed 0.4% (95%-CI = -0.2%-0.9%, p= 0.155) higher BrAce change during exercise for every ml kg-1 min-1 higher VO2peak. Differences of BrAce ratios during exercise were similar to fat oxidation rate changes, but without association to respiratory minute volume. Furthermore, the high-fit group showed higher maximum BrAce increase rates (46% h-1) in the late post-exercise phase compared to the lower-fit group (29% h-1). As a result, high-fit young, healthy individuals have a higher increase in BrAce concentrations related to submaximal exercise than lower-fit subjects, indicating a stronger exercise-related activation of fat metabolism.

[Gout and Its Management in Clinical Practice]. / Die Gicht und ihr Management in der Praxis.

Gout and Its Management in Clinical Practice Abstract. Resolution of an acute attack is usually the prime objective in routine clinical management of gout. Crystal identification in synovial fluid by polarised light microscopy is considered the diagnostic gold standard. Imaging procedures such as high-resolution ultrasonography are also useful. Non-steroidal anti-inflammatory drugs, steroids and colchicine (not approved in Switzerland, available from pharmacies) are used to treat an acute gout attack. Just as important as the diagnosis and treatment of an acute attack is the long-term management of hyperuricaemia in order to prevent further gout attacks as well as possible renal, cardiac or metabolic complications. Therefore, patients with a confirmed diagnosis of gout should, apart from non-pharmacologic interventions, receive hypouricaemic therapy with a target uric acid level of <360 µmol/l (<6 mg/dl). Drugs of first choice are xanthine oxidase inhibitors. Achievement of the therapeutic objective should be periodically reviewed, adjusting therapy as necessary.

Duodenal-Jejunal Bypass Liner (DJBL) Improves Cardiovascular Risk Biomarkers and Predicted 4-Year Risk of Major CV Events in Patients with Type 2 Diabetes and Metabolic Syndrome.

BACKGROUND: The duodenal-jejunal bypass liner (DJBL) represents a novel endoscopic minimally invasive treatment option for obesity-associated type 2 diabetes (T2D), affecting body weight and metabolic control. Until now, the effects of DJBL on cardiovascular risk have never been investigated. METHODS: Between 2012 and 2017, 71 patients with T2D and metabolic syndrome (MS) were recruited for implantation of DJBL for 9-12 months. Within DJBL treatment and a follow-up period of 6 months, patients were analysed for dynamics of cardiovascular biomarkers. Overall cardiovascular risk was estimated by the ADVANCE Risk Engine at time of implantation, explantation and 6 months after explantation of DJBL. RESULTS: DJBL-induced weight loss and improvements in blood sugar control were accompanied by significant decreases of the cardiovascular biomarkers high-sensitive CRP, lipoprotein-associated phospholipase A2 and small dense lipoprotein fraction LDL-4 (p = 0.001, p < 0.001 and p = 0.04, respectively). Estimated overall cardiovascular risk decreased significantly after DJBL implantation and remained stable within 6 months after explantation. CONCLUSIONS: In addition to beneficial effects of DJBL on weight loss, glycaemic control and lipid parameters in patients with MS, this is the first study that could further reveal significant impact on serological cardiovascular biomarkers and estimated CV risk, suggesting putative protective effects of DJBL on CV outcome.

Short-Term Effects of Growth Hormone on Lipolysis, Glucose and Amino Acid Metabolism Assessed in Serum and Microdialysate of Healthy Young Men.

OBJECTIVE: We investigated direct effects of a therapeutic growth hormone dose on lipolysis, glucose and amino acid metabolism. METHODS: This crossover microdialysis trial involved six healthy male volunteers receiving single subcutaneous injections of both growth hormone (0.035 mg/kg) and placebo (0.9% sodium chloride). The investigation comprised three test days with standard diet. The first day served for adaptation, the second and third one for determining study data during 9 night hours with or without growth hormone. Abdominal subcutaneous microdialysate and blood were continuously collected and forwarded to a separate room next door where hourly taken samples were centrifuged and frozen until analysed. RESULTS: Growth hormone achieved the peak serum level after 3 h followed by a plateau-like course for the next 6 h. Glycerol in microdialysate started to rise 2 h following growth hormone injection achieving significance compared to placebo after 9 h (P<0.05). Serum glycerol increased 4 h after growth hormone administration achieving significance after 6 h (P<0.05). Glucose and amino acid concentrations showed neither in microdialysate nor in serum significant differences between growth hormone and placebo. Serum values of insulin and C-peptide revealed no significant difference between growth hormone and placebo. SUMMARY AND CONCLUSION: As the result of a high single subcutaneous dose of GH, persistent lipolysis can be shown in continuously collected microdialysate and blood, but no indication for gluconeogenesis or protein anabolism.

Start low, go slowly - mental abnormalities in young prolactinoma patients under cabergoline therapy.

Background Prolactin-secreting pituitary adenomas in childhood and adolescence are rare. First-line therapy consists of dopamine agonists (DAs) like cabergoline. Experience in treating prolactinomas in paediatric and adolescent patients is limited. Methods This study was a retrospective analysis of clinical data, laboratory data, radiological findings and medical treatment of paediatric and adolescent patients with prolactinomas between 2009 and 2018. Results Our cohort of nine patients had a median age at diagnosis of 13 years (range 5-17). Main presenting symptoms were weight gain, disorders of the pituitary-gonadal axis and headache. Treatment with cabergoline resulted in a marked reduction in prolactin concentration in all nine patients. Tumour mass reduction was confirmed by magnetic resonance imaging (MRI) scan in seven patients. Noteworthy is that cabergoline therapy triggered frequent adverse effects in a total of eight patients - seven of whom suffered from mental disorders, five of whom had neurological symptoms and five of whom had gastrointestinal problems. The adverse effects occurred at a median dose of only 0.5 mg/week (range 0.25-2.0). Most symptoms were alleviated after the cabergoline dose was lowered. Therapy discontinuation was not necessary in any patient. Conclusions Cabergoline effectively lowers prolactin levels and may reduce tumour mass in paediatric and adolescent patients with prolactinomas. Potential adverse effects may include mental disorders and behavioural problems even at low cabergoline doses. Low starting doses and careful individual dose adjustments are required to enable therapy adherence.

Hemoglobin A1c and retinal arteriolar narrowing in children with type 1 diabetes: the diagnostics of early atherosclerosis risk in kids study.

BACKGROUND/OBJECTIVE: Microvascular alterations play a key role in the development of diabetes complications. Retinal vessel analysis is a unique method to examine microvascular changes in brain-derived vessels. METHODS: Sixty-seven pediatric and adolescent type 1 diabetes patients and 58 healthy control persons (mean age 12.4 ± 2.9 years) underwent non-mydriatic retinal photography of both eyes. Central retinal arteriolar and central retinal venular (CRVE) diameter equivalents as well as the arteriolar-to-venular ratio were calculated using a semiautomated software. All anthropometric and laboratory parameters were measured according to standardized procedures for children. RESULTS: Retinal vessel diameter did not differ between type 1 diabetic children and healthy controls. However, there was an independent association of higher hemoglobin A1c (HbA1c) levels with arteriolar narrowing. Arteriolar narrowing of 5.4 µm was observed with each percent increase in HbA1c. Longer duration of diabetes was associated with wider retinal arterioles. CRVE was not associated with diabetes duration or HbA1c. CONCLUSIONS: Microvascular arteriolar alterations are already present in childhood and may indicate subclinical atherosclerosis and increased risk of diabetes complications later in life. Future research will have to investigate the potential use of retinal vessel diameters for treatment monitoring and guidance of therapy in children.

Evaluating the four most important salivary sex steroids during male puberty: testosterone best characterizes pubertal development.

Background During pubertal development in healthy boys, increased levels of different sex steroids occur which are responsible for sexual maturation and physical changes. However, relationships between various sex hormones and pubertal development stages have not been sufficiently studied. Methods The investigation included 165 normal boys (mean age 12.7±2.8 years, mean body mass index [BMI] 19.6±4.2 kg/m2). Pubic hair (PH) stages were stratified by Tanner and testicular volume (TV) by means of the Prader orchidometer and assigned to the prepubertal, pubertal and postpubertal development phase. Four different sex steroids (testosterone [TE], dehydroepiandrosterone [DHEA]/dehydroepiandrosterone-sulfate [DHEAS], androstenedione (AE), 17-hydroxyprogesterone [17-OHP]) were measured in saliva by enzyme-linked immunosorbent assay (ELISA) and as serum total steroids by different assays (radioimmunoassay [RIA], chemiluminescence immunoassay [CLIA], electrochemiluminescence immunoassay [ECLIA]). Validation of saliva-based ELISA tests included data related to inter- and intra-assay coefficients of variation (CVs), recovery and linearity. Results Using Spearman rank correlation, salivary steroids significantly correlated (p<0.001) with pubertal development: TE (TV r=0.74 and PH stages r=0.72), DHEA (r=0.58 and 0.62), AE (r=0.38 and 0.45) and 17-OHP (r=0.42 and 0.43). Correlations between salivary and serum concentrations of steroids were also statistically significant (p<0.001). Binomial logistic regression analysis revealed significant correlations between salivary TE and pubertal maturation during the development phases of prepuberty-puberty and puberty-postpuberty. Inclusion of further salivary steroids did not improve analysis results. Conclusions Salivary TE permits a good non-invasive characterization of pubertal maturation stages. The consideration of further salivary sex steroids did not improve diagnostic accuracy.

Transfer of Topical Testosterone to Subcutaneous Microdialysate, Blood and Saliva in Healthy Young Men.

OBJECTIVE: We evaluated percutaneous penetration of topical testosterone and subsequent transfer to subcutaneous tissue, blood and saliva. METHODS: This microdialysis trial involved eight healthy male volunteers. Five participants received a single dose of 50 mg testosterone gel on the abdominal skin and three untreated participants served as controls. Two microdialysis probes were inserted percutaneously into the abdominal subcutaneous adipose tissue. On the skin above one probe, testosterone gel was applied (ipsilateral side). A second control probe was inserted on the contralateral side. For the determination of total and free testosterone, samples of subcutaneous microdialysate, serum, and saliva were collected over six hours, frozen, and analysed using ELISA procedures. RESULTS: Testosterone values in the ipsilateral microdialysate of treated subjects increased significantly within 6 h after gel application compared to controls. Salivary testosterone levels showed a rapid increase within 20 min after transdermal application followed by a plateau phase with tenfold increased testosterone levels. Microdialysate testosterone of the contralateral site started to rise moderately within the normal range 1 h after administration of testosterone gel whereas total and free testosterone serum concentrations increased within 2 h in each case followed by a plateau phase. SUMMARY AND CONCLUSION: Single topical administration of testosterone gel leads to a continuous increase of testosterone in the subcutaneous ipsilateral microdialysate. Rapid salivary testosterone increase happens after gel administration followed by tenfold increased testosterone plateau values. Despite continuous influx, testosterone concentrations in serum, saliva, and contralateral microdialysate show a plateau formation thus avoiding testosterone excess.

Lipoprotein-associated phospholipase A2 activity and low-density lipoprotein subfractions after a 2-year treatment with atorvastatin in adolescents with type 1 diabetes.

BACKGROUND: The objective of the study was to assess the effect of atorvastatin on inflammation markers and low-density lipoprotein (LDL) subfractions. METHODS: In a prospective, randomized, double-blind pilot study involving 28 adolescents with type 1 diabetes (T1D), lipoprotein-associated phospholipase A2 (Lp-PLA2) activity, high-sensitivity C-reactive protein (hsCRP), and subfractions of LDL were measured at baseline, after 1 year and 2 years of treatment with atorvastatin (10 mg/day) vs. placebo. RESULTS: For the atorvastatin group, we found posttreatment reductions of Lp-PLA2 activity (p<0.001), LDL cholesterol (p=0.001), non-small dense LDL cholesterol (p<0.001), total cholesterol (p<0.001), and apolipoprotein B (apo B) (p<0.001), whereas small dense LDL cholesterol and hsCRP did not change significantly. CONCLUSIONS: In adolescents with T1D, long-term treatment with atorvastatin is safe and may reduce cardiovascular risk by significant decreases of Lp-PLA2 activity and LDL cholesterol.

Decrease of small dense LDL and lipoprotein-associated phospholipase A2 due to human growth hormone treatment in short children with growth hormone deficiency and small for gestational age status.

BACKGROUND: Growth hormone deficiency (GHD) and small for gestational age (SGA) status are associated with cardiovascular risks. We therefore, investigated antiatherogenic effects of growth hormone (GH). METHODS: Subfractions of low-density lipoprotein (LDL) and high-density lipoprotein (HDL), lipoprotein-associated phospholipase A2 (Lp-PLA2), and high-sensitivity C-reactive protein (hsCRP) were measured at baseline, after 8 and 52 weeks of GH treatment in 51 short children born SGA (n=33) or with GHD (n=18). RESULTS: The overall group showed post-treatment reductions of LDL cholesterol (LDL-C) (p=0.016), small-dense LDL cholesterol (sdLDL-C, p<0.001), Lp-PLA2 (p<0.001), and hsCRP (p=0.005), but increase of HDL2a cholesterol (HDL2a-C, p=0.025). SGA children revealed significant correlations between Lp-PLA2 and LDL-C and sdLDL-C both before and after GH, significant reductions of sdLDL-C, Lp-PLA2, hsCRP, and an increase of HDL2a-C. GHD children showed the same lipid responses, though not significantly. CONCLUSIONS: Children with GHD or born SGA may benefit from GH by growth acceleration and reduction of cardiovascular long-term risks.

Non-High-Density Lipoprotein Cholesterol in Children with Diabetes: Proposed Treatment Recommendations Based on Glycemic Control, Body Mass Index, Age, Sex, and Generally Accepted Cut Points.

Percentile-based non-high-density lipoprotein cholesterol levels were analyzed by glycemic control, weight, age, and sex of children with type 1 diabetes (n = 26,358). Ten percent of all children and 25% of overweight adolescent girls require both immediate lipid-lowering medication and lifestyle changes to achieve non-high-density lipoprotein cholesterol levels <120 mg/dL and cardiovascular risk reduction.

'Sportmotorische Bestandesaufnahme': criterion- vs. norm-based reference values of fitness tests for Swiss first grade children.

Health is closely linked to physical activity and fitness. It is therefore important to monitor fitness in children. Although many reports on physical tests have been published, data comparison between studies is an issue. This study reports Swiss first grade norm values of fitness tests and compares these with criterion reference data. A total of 10,565 boys (7.18 ± 0.42 years) and 10,204 girls (7.14 ± 0.41 years) were tested for standing long jump, plate tapping, 20-m shuttle run, lateral jump and 20-m sprint. Average values for six-, seven- and eight-year-olds were analysed and reference curves for age were constructed. Z-values were generated for comparisons with criterion references reported in the literature. Results were better for all disciplines in seven-year-old first grade children compared to six-year-old children (p < 0.01). Eight-year-old children did not perform better compared to seven-year-old children in the sprint run (p = 0.11), standing long jump (p > 0.99) and shuttle run (p = 0.43), whereas they were better in all other disciplines compared to their younger peers. The average performance of boys was better than girls except for tapping at the age of 8 (p = 0.06). Differences in performance due to testing protocol and setting must be considered when test values from a first grade setting are compared to criterion-based benchmarks. In a classroom setting, younger children tended to have better results and older children tended to have worse outcomes when compared to their age group criterion reference values. Norm reference data are valid allowing comparison with other data generated by similar test protocols applied in a classroom setting.

Decreased levels of homoarginine and asymmetric dimethylarginine in children with type 1 diabetes: associations with cardiovascular risk factors but no effect by atorvastin.

OBJECTIVES: To investigate homoarginine and asymmetric dimethylarginine (ADMA) in controls compared to children with type 1 diabetes (T1D) and if homoarginine and ADMA are affected by atorvastatin. METHODS: Homoarginine and ADMA levels of 28 T1D patients were compared to levels of 41 controls. In T1D patients, homoarginine and ADMA were determined at baseline, 1 year, and 2 years at daily 10 mg atorvastatin or placebo within a double-blind study. RESULTS: At baseline, both homoarginine and ADMA were lower (p<0.001) in T1D patients compared to controls. In T1D patients, homoarginine and ADMA were not influenced by atorvastatin. Inverse correlations between homoarginine and HbA1c (p<0.001) and between ADMA and systolic blood pressure (p=0.005) and pulse pressure (p=0.003) were shown. CONCLUSIONS: Homoarginine and ADMA levels are decreased and associated with cardiovascular risk factors in children with T1D without being affected by atorvastatin.

Algorithm-based cholesterol monitoring in children with type 1 diabetes.

OBJECTIVE: To facilitate child-specific and diabetes-related cholesterol control, we developed a monitoring algorithm derived from population-based reference values. STUDY DESIGN: Low-density lipoprotein (LDL)-, non-high-density lipoprotein (HDL)-, and HDL cholesterol percentile values were calculated for children with type 1 diabetes (T1D) and their peers without T1D within algorithm-based categories of sex, age: 1-10 vs >10-<18 years, body mass index: <90th vs ≥90th percentile, and hemoglobin A1c <6%, 6%-<7.5%, 7.5%-9%, >9%. Analyses included 26 147 patients sampled from a German/Austrian population-based registry for T1D (Diabetes Documentation and Quality Management System) and 14 057 peers without diabetes participating in the national Health Interview and Examination Survey for Children and Adolescents in Germany. RESULTS: Reference percentile values for cholesterol were derived as a diagnostic algorithm aimed at supporting long-term cholesterol control. Taking account of a patient's sex, age-group, weight-, and hemoglobin A1c-category, the flowcharts of the algorithm developed separately for LDL-, non-HDL-, and HDL cholesterol allow comparing his/her cholesterol levels with population-based reference percentile values of peers without T1D. CONCLUSIONS: The population-based algorithmic approach applied to LDL-, non-HDL-, and HDL cholesterol allows referencing children with T1D with regard to their peers without T1D and, if necessary, suggests corrections of glycemic control to optimize long-term cholesterol levels.