It is Time to Screen for Homozygous Familial Hypercholesterolemia in the United States.

Homozygous familial hypercholesterolemia (HoFH) is an ultra-rare inherited condition that affects approximately one in 300,000 people. The disorder is characterized by extremely high, life-threatening levels of low-density lipoprotein (LDL) cholesterol from birth, leading to significant premature cardiovascular morbidity and mortality, if left untreated. Homozygous familial hypercholesterolemia is severely underdiagnosed and undertreated in the United States (US), despite guidelines recommendations for universal pediatric lipid screening in children aged 9-11. Early diagnosis and adequate treatment are critical in averting premature cardiovascular disease in individuals affected by HoFH. Yet, an unacceptably high number of people living with HoFH remain undiagnosed, misdiagnosed, and/or receive a late diagnosis, often after a major cardiovascular event. The emergence of novel lipid-lowering therapies, along with the realization that diagnosis is too often delayed, have highlighted an urgency to implement policies that ensure timely detection of HoFH in the US. Evidence from around the world suggests that a combination of universal pediatric screening and cascade screening strategies constitutes an effective approach to identifying heterozygous familial hypercholesterolemia (HeFH). Nevertheless, HoFH and its complications manifest much earlier in life compared to HeFH. To date, little focus has been placed on the detection of HoFH in very young children and/or infants. The 2023 Updated European Atherosclerosis Society Consensus Statement on HoFH has recommended, for the first time, broadening pediatric guidelines to include lipid screening of newborn infants. Some unique aspects of HoFH need to be considered before implementing newborn screening. As such, insights from pilot studies conducted in Europe may provide some preliminary guidance. Our paper proposes a set of actionable measures that states can implement to reduce the burden of HoFH. It also outlines key research and policy gaps that need to be addressed in order to pave the way for universal newborn screening of HoFH in the US.

Newborn screening for lipid disorders.

PURPOSE OF REVIEW: Newborn screening is one of the most successful public health programs of the last century and offers unparalleled access to universal screening for a variety of metabolic and other disorders. Interest in development of newborn screening for lipid disorders has intensified in recent years. Screening newborns for lipid disorders has important implications for the health of the newborn as well as their relatives, and in the case of more common lipid disorders like familial hypercholesterolemia, could have important public health implications. RECENT FINDINGS: Recent studies have demonstrated feasibility of measuring biomarkers for heterozygous familial hypercholesterolemia from newborn screening dried blood spot specimens. Another lipid disorder, cerebrotendinous xanthomatosis, is currently amenable to newborn screening utilizing currently available assays. New research in next-generation sequencing as a primary screen in newborns will also identify both common and rare lipid disorders in newborns. SUMMARY: Historically, newborn screening for lipid disorders was not done for many reasons, but new research has developed testing methods that may successfully identify common and rare lipid disorders. This will impact the health of the newborn but could also impact family members and public health.

Familial Hypercholesterolemia Biomarker Distribution in Dried Blood Spots.

OBJECTIVE: To evaluate distribution profiles of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B (apoB) as candidate markers of familial hypercholesterolemia in newborns, taking into consideration potential confounding factors, such as gestational age, birth weight, sex, and race. STUDY DESIGN: TC, LDL-C, and apoB were measured from 10 000 residual deidentified newborn dried blood spot cards. Concentrations for each biomarker were reported as multiples of the median, with emphasis on describing the 99th percentile values based on birth weight, gestational age, sex, and race. Seasonal variation of biomarkers was also explored. RESULTS: LDL-C and apoB had distribution curves with tails showing extreme elevation, whereas the distribution of TC was less elevated and had the smallest range. Neonates born at early gestational age and low birth weight had significantly greater 99th percentile of multiples of the median values for apoB but not TC or LDL-C. Differences in biomarker concentration based on sex and race were minimal. All biomarkers showed greatest concentrations in the winter as compared with summer months. CONCLUSIONS: LDL-C and apoB had distribution curves supporting candidacy for neonatal familial hypercholesterolemia screening. Future studies are needed to correlate newborn screening results with molecular testing to validate these 2 biomarkers, along with measured cholesterol levels later in childhood.

Parental Attitudes and Ideas Regarding Newborn Screening for Familial Hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) is an inherited disease which causes premature atherosclerotic cardiovascular disease. However, less than 10% of individuals with FH have been identified. OBJECTIVE: To assess parental perspectives for inclusion of FH on routine newborn screening (NBS) and to highlight potential benefits, harms, and ethical concerns. METHODS: Telephone interviews of two groups were conducted: 1) parents of children diagnosed with FH, and 2) parents of children diagnosed with a genetic condition through NBS. Stratified purposive sampling was used to ensure adequate representation. The 11 telephone interviews were conducted in 30-min sessions guided by a semi-structured interview script. At the beginning of the interview, participants were educated on the NBS process and FH. The interviews were transcribed verbatim, and a thematic analysis was performed in multiple steps. RESULTS: All interviewees indicated that they would be interested in having their child be screened for FH on the newborn screen. Reasons supporting screening during the newborn period included knowing their child's diagnosis, the ability to screen family members for FH, incorporation of lifestyle changes, and access to preventive care. Negatives surrounding screening during the newborn period included increased stress or anxiety, knowledge, stigma, and the delay from diagnosis to initiation of pharmacotherapy for FH. CONCLUSION: While these interviewees were in favor of NBS for FH, further education of parents and clinicians is needed to ensure proper implementation. The results of this study may be useful to formulate family notification and care protocols for newborns diagnosed with FH and other diseases.

What is already known on this subject? Familial hypercholesterolemia is a common inherited disorder that predisposes to early cardiovascular disease, but most affected individuals are not diagnosed. Childhood cholesterol screening is an effective but underutilized diagnostic tool. Previous studies report parents find childhood cholesterol screening acceptable, but it is not known if screening newborns would also be acceptable.What does this study add? Interviewees found screening newborns for familial hypercholesterolemia acceptable and would agree to screen their own newborn. The ability to screen other family members and access to early treatment were important factors in their decision to screen. Education of clinicians about familial hypercholesterolemia was an important concern raised by interviewees.

Preventive Medicine in Pediatric Cardiology Practice.

OBJECTIVES: The objective of the study was to assess contemporary practice patterns of pediatric cardiologists with respect to cholesterol disorders and smoking-related illness. STUDY DESIGN: We sent 2 anonymous surveys to the members of the American Academy of Pediatrics Section on Cardiology and Cardiac Surgery and the Pediheart online community. The surveys addressed training in and management of cholesterol disorders and smoking-related illness. RESULTS: There were 97 responses to the cholesterol disorders survey. A total of 51.6% reported little or no formal training on cholesterol disorders. A total of 56.4% underestimated the prevalence of familial hypercholesterolemia by at least twofold. A total of 54.7% were at least somewhat comfortable prescribing statins. In 5 clinical vignettes, respondents frequently gave clinical recommendations in line with the 2019 American Heart Association guidelines although both undertreatment and overtreatment were recommended. There were 90 responses to the survey on smoking-related illness. Little or no formal training in nicotine addiction (52.3%) or smoking cessation (60.5%) was reported by respondents. Respondents screened for tobacco use in less than a one-third of hospitalizations and less than two-thirds of outpatient clinic visits. Screening for exposure to secondhand smoke was even less common. Twenty-seven percent of respondents never recommend a household smoking ban for their patients. A total of 83.3% were uncomfortable prescribing medications for their patients for smoking cessation, and 65.5% rarely or never refer patients for smoking cessation assistance. CONCLUSION: Although positioned to address the childhood origins of adult heart disease, those cardiologists surveyed placed a limited emphasis on cholesterol disorders and smoking-related disease in their clinical practice.

Rationale and design of two trials assessing the efficacy, safety, and tolerability of inclisiran in adolescents with homozygous and heterozygous familial hypercholesterolaemia.

BACKGROUND: Inclisiran is a small interfering RNA molecule that reduces low-density lipoprotein cholesterol (LDL-C) by inhibition of proprotein convertase subtilisin/kexin type 9. This subcutaneous, twice-yearly administered agent has been shown to effectively and safely lower LDL-C in adult patients with established atherosclerotic cardiovascular disease, adults at high risk for atherosclerotic cardiovascular disease, as well as in adults with heterozygous familial hypercholesterolaemia. With the current, limited treatment options available to reach treatment goals in children with severe heterozygous familial hypercholesterolaemia, homozygous familial hypercholesterolaemia, or statin intolerance, inclisiran could be a valuable new therapeutic option. OBJECTIVES: The objective of these ongoing studies is to investigate the efficacy, safety, and tolerability of inclisiran in adolescents diagnosed with homozygous familial hypercholesterolaemia (ORION-13) or heterozygous familial hypercholesterolaemia (ORION-16). STUDY DESIGN: ORION-13 and ORION-16 are both two-part (1-year double-blind inclisiran vs. placebo/1 year open-label inclisiran) multicentre trials including adolescents aged 12 to <18 years diagnosed with familial hypercholesterolaemia. ORION-13 will include ∼12 participants diagnosed with homozygous familial hypercholesterolaemia and ORION-16 will include ∼150 participants diagnosed with heterozygous familial hypercholesteroleamia. The primary endpoint is the percentage change in LDL-C from baseline to Day 330. Secondary efficacy and safety endpoints include changes in other lipid parameters and treatment-emergent adverse events as well as laboratory parameters and vital signs. Exploratory endpoints include individual responsiveness of the participants and change in LDL-C according to the type of underlying causal mutation. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov/. Unique identifier: NCT04659863 (ORION-13) and NCT04652726 (ORION-16).

Practices and Attitudes Regarding Pediatric Cholesterol Screening Recommendations Differ Between Pediatricians and Family Medicine Clinicians.

Pediatricians had higher rates of ordering pediatric cholesterol screening than family medicine (FM) clinicians. This study aims to compare knowledge, attitude, and practices of clinicians' pediatric cholesterol screening practices and attitudes between these two specialties. A 14-item electronic survey using Likert scales was sent to all clinicians in the institution's Departments of Pediatrics and FM between 2018 and 2019. Chi-square and t-tests were used to compare pediatricians and FM clinicians. 22 clinicians from Pediatrics and 111 from FM completed the survey. Compared to FM clinicians, pediatricians were more familiar with the National Heart, Lung, and Blood Institute guidelines, which are more vigorous in their recommendation of universal cholesterol screening. Pediatricians reported being more supportive of universal cholesterol screening in children (p < 0.05). In practice, pediatricians reported screening almost two thirds (64.8%) of eligible patients during the past year, while FM clinicians reported screening approximately one third (34.1%) of eligible patients (p < 0.001). Pediatricians were more likely to screen based on patient-specific risk factors and their practice decisions were more heavily influenced by published guidelines, institutional education, availability of non-fasting blood to be used for screening, and the availability of an institutional pediatric lipid clinic (p < 0.05). The differences in knowledge, attitudes, and practices of cholesterol screening may contribute to different screening rates among clinicians from FM and pediatrics. To improve patient care and reduce gaps, it is important to implement interventions at the institutional level as well as to adopt uniform guideline recommendations at the national level.

Awareness, diagnosis and treatment of heterozygous familial hypercholesterolemia (HeFH) - Results of a US national survey.

BACKGROUND: HeFH is a common inherited disorder that leads to markedly elevated LDL-cholesterol from birth and premature cardiovascular disease. HeFH is frequently underdiagnosed and undertreated. OBJECTIVE: To compare how well primary care physicians and cardiologists recognize and treat HeFH. METHODS: The National Lipid Association surveyed 500 primary care physicians and 500 cardiologists in the US who have patients with baseline LDL-cholesterol ≥ 190 mg/dL. The survey was conducted between August 29 and September 30, 2019. RESULTS: For a hypothetical case of HeFH, 57% of cardiologists versus 43% of primary care physicians made the correct diagnosis (P<0.001). Among respondents, 21% of cardiologists versus 29% of primary care physicians have never made a diagnosis of HeFH in a patient with an LDL-cholesterol ≥ 190 mg/dL (P<0.004). Only 7% of cardiologists versus 5% of primary care physicians would refer to a lipid specialist (P=0.05). For additional LDL-cholesterol lowering after statins, 58% of cardiologists versus 48% of primary care physicians would prescribe a PCSK9 inhibitor (P=0.004); however, 30% of cardiologists versus 53% of primary care physicians have never prescribed a PSCK9 inhibitor in an HeFH patient (P<0.001). CONCLUSION: Although cardiologists compared to primary care physicians are somewhat more likely to recognize and treat HeFH patients according to guidelines, both physician specialties do not adequately recognize or treat HeFH. There is a need for more education and training in recognizing and treating HeFH, greater access to lipid specialists, and fewer barriers for PCSK9 inhibitor use.

Prevention of Atherosclerotic Cardiovascular Disease in Children with Familial Hypercholesterolemia.

PURPOSE OF REVIEW: Familial hypercholesterolemia (FH), a common inherited disorder of LDL-C metabolism that predisposes to premature cardiovascular disease, is underdiagnosed. Despite recommendations for screening all children and initiation of lipid-lowering medication beginning at 8-10 years of age, adherence to guidelines is low. Most individuals with FH are inadequately treated, especially women and children. The purpose of this review is to discuss current literature and recommendations for the diagnosis and treatment of heterozygous FH (HeFH) in the pediatric population. RECENT FINDINGS: Twenty-year outcome data demonstrate lower rates of atherosclerotic cardiovascular disease (ASCVD) related events and death in individuals with FH who were treated with statins from childhood, compared to those who initiated statins in adulthood. While diagnosis rates of FH are slowly improving, most clinicians do not adhere to recommendations for cholesterol screening in youth. Identifying youth with FH offers the opportunity for early intervention to prevent ASCVD and identify affected relatives through reverse cascade screening.

Cost-Effectiveness Analysis of Michigan's School-Wide Sexually Transmitted Disease Screening Program in Four Detroit High Schools.

PURPOSE: The Michigan Department of Health and Human Services, in collaboration with St. John Providence Health System, initiated voluntary school-wide sexually transmitted disease (STD) screenings in four Detroit public high schools. We sought to assess the cost-effectiveness of the STD screening program from 2010 to 2015, with a focus on chlamydia. METHODS: The costs and effectiveness of the school-based screening were compared with those of a "no school screening" scenario using a healthcare system perspective. A decision tree model was constructed to project cases of chlamydia, epididymitis, and pelvic inflammatory disease (PID) in each of the two scenarios among students tested positive and their partners. Health effects were measured as cases of PID prevented, and quality-adjusted life-years (QALYs) gained. Cost estimates included program costs, chlamydia testing/treatment costs in the absence of school screening, and treatment costs for epididymitis, PID, and PID sequelae. The incremental cost-effectiveness ratio (ICER) was measured as cost/QALY gained. Multivariate sensitivity analyses were conducted on key parameter estimates and assumptions used. RESULTS: Under base-case assumptions, at a total program cost of $333,848 over 5 years, the program prevented an estimated 1.9 cases of epididymitis and 17.3 cases of PID, resulting in an ICER of $38,235/QALY gained (yearly ICER ranging from $27,417 to $50,945/QALY). Of 10,000 Monte Carlo simulation runs, the yearly ICER remained ≤$50,000/QALY in 64%-98% of the simulation runs. CONCLUSIONS: We found favorable cost-effectiveness ratios for Michigan's school-wide STD screening program in Detroit. School-based STD screening programs of this type warrant careful considerations by policy makers and program planners.

Differences in pediatric cholesterol screening rates between family physicians and pediatricians correlate with conflicting guidelines.

Conflicting guidelines regarding universal pediatric cholesterol screening were released between 2011 and 2019, but the impact on screening rates remains understudied. The purpose of this study was to examine trends in pediatric cholesterol screening rates within a single institution in the United States and their association with release of national guidelines, local educational tools, and electronic health record (EHR) modifications. Order placement was defined as ordering a high-density lipoprotein cholesterol level in a patient aged 9-21 years with ≥1 well visit in prior 3 years. Order placement rate (OPR) was calculated per month using 3 months' moving average smoothing and analyzed based on date, patient age, and specialty of ordering clinician. Timing of educational tools, EHR modifications, and national guideline release were analyzed for changes in OPR. Prior to release of 2011 guidelines recommending universal pediatric cholesterol screening, pediatrician OPR was 35% (95% CI: 29-43%) compared to 8% (7-11%) for family physicians. For both specialties, OPR increased after 2011 guidelines, educational initiatives, and EHR changes, but decreased after 2016, with a larger decrease for family physicians (p < 0.001 for all). OPR was consistently higher for pediatricians than for family physicians during the study period, with largest OPR changes correlating with release of guidelines. The findings from the study suggest that conflicting guidelines may contribute to lower overall OPR, and to different screening rates for children cared for by pediatricians compared to family physicians.

Reported Chlamydia and Gonorrhea Are Decreasing Among Young Black Women: Good News or Bad News? A Narrative Review.

ABSTRACT: Since 2010, reported chlamydia and gonorrhea rates decreased among Black women aged 15 to 19 years and were stable for Black women aged 20 to 24 years in the United States. Rates increased for older Black women aged 25 to 39 years and all White women. The Black/White rate ratio decreased across age groups. We examined whether trends in reported rates reflected changing prevalence or changing screening. We analyzed trends in reported chlamydia and gonorrhea rates from 2010 to 2018 among women in the United States aged 15 to 39 years by age and race/ethnicity subgroup, state, and reporting source. Most jurisdictions reported decreased chlamydia and gonorrhea rates among Black teens and increased rates among White teens and older women. Between 2010 and 2018, public clinics reported fewer cases, especially among young Black women, that were not restored by increases elsewhere. We reviewed literature on trends in screening, prevalence, and sequelae. Family planning clinics annual reports showed chlamydia tests among women younger than 25 years decreased by 541,573 tests (-38%) in 2018 compared with 2010 and the number of women visiting sexually transmitted disease clinics had decreased 50% by 2016 compared with 2010. Prevalence of chlamydia in a sentinel population (Job Corps) was unchanged for Black women younger than 25 years and increased for Whites aged 20 to 24 years. Sequelae trends using data from a large all-payer emergency department database were mixed: pelvic inflammatory disease decreased, whereas ectopic pregnancy increased. Decreases in testing at public clinics likely missed diagnoses among young Black women, a group traditionally at highest risk and in need of more testing. Innovative approaches to screening are needed.

Perceptions and Barriers on the Use of Proprotein Subtilisin/Kexin Type 9 Inhibitors in Heterozygous Familial Hypercholesterolemia (From a Survey of Primary Care Physicians and Cardiologists).

Heterozygous familial hypercholesterolemia (HeFH) results in significant elevations in LDL-C and premature atherosclerotic cardiovascular disease (ASCVD). Current guidelines recommend add-on proprotein subtilisin/kexin type 9 inhibitor (PCSK9i) therapy for additional LDL-C lowering beyond statins. Data are sparse, however, regarding treatment patterns and barriers relating to PCSK9i in HeFH patients. We examined physician attitudes, use, and barriers for treatment in patients with HeFH. We surveyed 1,000 physicians (500 primary care providers [PCPs] and 500 cardiologists in the US regarding their preferred treatments, experience and barriers associated with using PCSK9is. Cardiologists compared to PCPs were more likely to rank a PCSK9i as most important for an HeFH patient needing additional LDL-C lowering (68.6% vs. 64.8%; p <0.05), as well as prescribing and having a patient on a PCSK9i. PCPs vs. cardiologists were less likely (odds ratio [OR] [95% confidence interval] = 0.46 [0.34-0.63]), private vs. academic practice more likely (OR = 1.53 [1.02-2.28]), and those who would prescribe a PCSK9i in an HeFH patient with (OR = 3.86 [2.57-5.78]) or without (OR = 1.96 [1.40-2.72]) ASCVD needing additional LDL-C reduction beyond a statin were more likely to actually prescribe a PCSK9i. Those practicing in an urban vs. rural setting were less likely (OR = 0.56 [0.34-0.93]), and those indicating they would prescribe a PCKS9i in an HeFH patient with (OR = 2.80 [1.74-4.49]) or without (OR = 1.43 [1.02-2.02]) ASCVD needing additional LDL-C lowering beyond a statin were more likely to face difficulty prescribing a PCSK9i (all p <0.05 to p <0.01). Greater physician education and assistance among both cardiologists and PCPs are needed to address the gaps in understanding and treatment regarding PCSK9is.

Children with Heterozygous Familial Hypercholesterolemia in the United States: Data from the Cascade Screening for Awareness and Detection-FH Registry.

OBJECTIVE: To describe enrollment characteristics of youth in the Cascade Screening for Awareness and Detection of FH Registry. STUDY DESIGN: This is a cross-sectional analysis of 493 participants aged <18 years with heterozygous familial hypercholesterolemia recruited from US lipid clinics (n = 20) between April 1, 2014, and January 12, 2018. At enrollment, some were new patients and some were already in care. Clinical characteristics are described, including lipid levels and lipid-lowering treatments. RESULTS: Mean age at diagnosis was 9.4 (4.0) years; 47% female, 68% white and 12% Hispanic. Average (SD) highest Low-density lipoprotein cholesterol (LDL-C) was 238 (61) mg/dL before treatment. Lipid-lowering therapy was used by 64% of participants; 56% were treated with statin. LDL-C declined 84 mg/dL (33%) among those treated with lipid-lowering therapy; statins produced the greatest decline, 100 mg/dL (39% reduction). At enrollment, 39% had reached an LDL-C goal, either <130 mg/dL or ≥50% decrease from pre-treatment; 20% of those on lipid-lowering therapy reached both goals. CONCLUSIONS: Among youth enrolled in the Cascade Screening for Awareness and Detection of FH Registry, diagnosis occurred relatively late, only 77% of children eligible for lipid-lowering therapy were receiving treatment, and only 39% of those treated met their LDL-C goal. Opportunities exist for earlier diagnosis, broader use of lipid-lowering therapy, and greater reduction of LDL-C levels.

MAPK activity dynamics regulate non-cell autonomous effects of oncogene expression.

A large fraction of human cancers contain genetic alterations within the Mitogen Activated Protein Kinase (MAPK) signaling network that promote unpredictable phenotypes. Previous studies have shown that the temporal patterns of MAPK activity (i.e. signaling dynamics) differentially regulate cell behavior. However, the role of signaling dynamics in mediating the effects of cancer driving mutations has not been systematically explored. Here, we show that oncogene expression leads to either pulsatile or sustained ERK activity that correlate with opposing cellular behaviors (i.e. proliferation vs. cell cycle arrest, respectively). Moreover, sustained-but not pulsatile-ERK activity triggers ERK activity waves in unperturbed neighboring cells that depend on the membrane metalloprotease ADAM17 and EGFR activity. Interestingly, the ADAM17-EGFR signaling axis coordinates neighboring cell migration toward oncogenic cells and is required for oncogenic cell extrusion. Overall, our data suggests that the temporal patterns of MAPK activity differentially regulate cell autonomous and non-cell autonomous effects of oncogene expression.

In animals, the MAPK pathway is a network of genes that helps a cell to detect and then respond to an external signal by switching on or off a specific genetic program. In particular, cells use this pathway to communicate with each other. In an individual cell, the MAPK pathway shows fluctuations in activity over time. Mutations in the genes belonging to the MAPK pathway are often one of the first events that lead to the emergence of cancers. However, different mutations in the genes of the pathway can have diverse effects on a cell's behavior: some mutations cause the cell to divide while others make it migrate. Recent research has suggested that these effects may be caused by changes in the pattern of MAPK signaling activity over time. Here, Aikin et al. used fluorescent markers to document how different MAPK mutations influence the behavior of a human breast cell and its healthy neighbors. The experiments showed that cells with different MAPK mutations behaved in one of two ways: the signaling quickly pulsed between high and low levels of activity, or it remained at a sustained high level. In turn, these two signaling patterns altered cell behavior in different ways. Pulsed signaling led to more cell division, while sustained signaling stopped division and increased migration. Aikin et al. then examined the effect of the MAPK mutations on neighboring healthy cells. Sustained signaling from the cancerous cell caused a wave of signaling activity in the surrounding cells. This led the healthy cells to divide and migrate toward the cancerous cell, pushing it out of the tissue layer. It is not clear if these changes protect against or promote cancer progression in living tissue. However, these results explain why specific cancer mutations cause different behaviors in cells.

Phenotypic Variability in Atherosclerosis Burden in an Old-Order Amish Family With Homozygous Sitosterolemia.

Sitosterolemia is a rare atherogenic sterol storage disease with variability in its presentation requiring a high degree of clinical suspicion. We present 8 cases of sitosterolemia from an Amish kindred that, despite a background of decreased genetic and lifestyle variability, still had markedly variable presentations. (Level of Difficulty: Advanced.).

Early hMSC morphology and proliferation on model polyelectrolyte multilayers.

Polyelectrolyte multilayers (PEMs) are a category of materials commonly used as coatings on surfaces that interact with cells. The properties of PEMs have been established to be controlled by not only polyelectrolyte choice, but by the identity of the initially applied (bottom) layer. In this work, 5-bilayer PEMs consisting of poly(diallyldimethylammonium chloride) (PDADMAC) and poly(sodium 4-styrenesulfonate) (PSS) were coated on gold-sputtered quartz substrates with different first layer materials. A final poly-l-lysine (PLL) layer was added to all PEMs to provide identical top layers conducive to cell growth. As in previous work, initial layer selection affected PEM roughness. All coated surfaces, including the PLL-only control, showed increased dispersive surface energy but decreased polar surface energy, as compared to uncoated surfaces. When human mesenchymal stem cells (hMSCs) were cultured on these surfaces, analysis through lateral cell imaging for the first 90 min and fluorescent staining after 1 day showed improved attachment on surfaces with a PDADMAC bottom layer. However, after 4 days, a higher cell density was observed on the PLL-only and uncoated control surfaces, indicating that the PEMs negatively affected hMSC proliferation. Both the long and short time period results did not correlate to any of the roughness and surface energy trends, indicating more complex interactions between the cells and the surface relating to charge distribution and functional group density.

Novel Lipid Thresholds for Screening Predict the Need for Pharmacotherapy.

OBJECTIVE: To identify non-high-density lipoprotein cholesterol (HDL-C) and HDL-C thresholds for pediatric nonfasting lipid screens that are more predictive of the need for lipid-lowering pharmacotherapy and estimate numbers of potentially avoidable fasting lipid panels. STUDY DESIGN: In this retrospective review of children and youths aged 8-21 years presenting for preventive cardiology care, initial lipid results, recommendations for pharmacotherapy, and presence of additional cardiovascular risk factors were noted. Receiver operating characteristic curve analysis calculated threshold lipid values predicting the need for pharmacotherapy and were applied to 2 screening populations. Rates of potentially unnecessary fasting lipid panels were calculated. RESULTS: A non-HDL-C value >156 mg/dL for children with ≥1 cardiovascular risk factors and >199 mg/dL for children without risk factors conferred 95% or greater sensitivity in predicting a recommendation for pharmacotherapy with higher specificity, positive predictive value, and negative predictive value compared with current guidelines. HDL-C was a poor predictor of pharmacotherapy. Application of the current thresholds to screening populations indicated that 38.5%-92.3% of follow-up fasting lipid panels would not result in pharmacotherapy. CONCLUSION: Using higher non-HDL-C and lower HDL-C thresholds could prevent unnecessary follow-up lipid panels and reduce patient anxiety, cost, and time. This could improve compliance with universal pediatric lipid screening for both health care providers and families.

In pediatric familial hypercholesterolemia, lipoprotein(a) is more predictive than LDL-C for early onset of cardiovascular disease in family members.

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) level and lipoprotein(a) [Lp(a)] ≥ 50 mg/dL predict atherosclerotic cardiovascular disease (ASCVD) risk in adults with familial hypercholesterolemia (FH), but their role for children with FH is less clear. OBJECTIVE: This study examined the relationship between elevated Lp(a) and LDL-C levels in a pediatric population with FH and onset of ASCVD in family members. METHODS: Retrospective review of pediatric patients with FH identified LDL-C, Lp(a), and family history of ASCVD. Logistic regression modeling evaluated the association between the child's Lp(a) and peak LDL-C level with earliest age of ASCVD onset in their family. RESULTS: One hundred twenty-nine children from 109 families were identified. Children from families with early-onset ASCVD were 3 times more likely to have high Lp(a) than those with a family history of late-onset ASCVD (OR: 3.77, 95% CI: 1.16-12.25, P = .027) but were not more likely to have highly elevated peak LDL-C (≥190 mg/dL) (OR: 0.45, 95% CI: 0.11-1.80, P = .26). CONCLUSION: Children with FH and family history of early-onset ASCVD were more likely to have Lp(a) ≥50 mg/dL than children with FH and family history of late-onset ASCVD. Family history of early-onset ASCVD was more predictive of a child's Lp(a) level than of a child's peak LDL-C. Measurement of Lp(a) in children with FH may better characterize their cardiovascular risk, particularly when knowledge of family history is limited. Lp(a) testing may also identify children with FH that could benefit from more aggressive management to reduce ASCVD risk.