Heparin resistance in COVID-19 patients in the intensive care unit.

Patients with COVID-19 have a coagulopathy and high thrombotic risk. In a cohort of 69 intensive care unit (ICU) patients we investigated for evidence of heparin resistance in those that have received therapeutic anticoagulation. 15 of the patients have received therapeutic anticoagulation with either unfractionated heparin (UFH) or low molecular weight heparin (LMWH), of which full information was available on 14 patients. Heparin resistance to UFH was documented in 8/10 (80%) patients and sub-optimal peak anti-Xa following therapeutic LMWH in 5/5 (100%) patients where this was measured (some patients received both anticoagulants sequentially). Spiking plasma from 12 COVID-19 ICU patient samples demonstrated decreased in-vitro recovery of anti-Xa compared to normal pooled plasma. In conclusion, we have found evidence of heparin resistance in critically unwell COVID-19 patients. Further studies investigating this are required to determine the optimal thromboprophylaxis in COVID-19 and management of thrombotic episodes.

Analysis of Left Atrial Respiratory and Cardiac Motion for Cardiac Ablation Therapy.

Cardiac ablation therapy is often guided by models built from preoperative computed tomography (CT) or magnetic resonance imaging (MRI) scans. One of the challenges in guiding a procedure from a preoperative model is properly synching the preoperative models with cardiac and respiratory motion through computational motion models. In this paper, we describe a methodology for evaluating cardiac and respiratory motion in the left atrium and pulmonary veins of a beating canine heart. Cardiac catheters were used to place metal clips within and near the pulmonary veins and left atrial appendage under fluoroscopic and ultrasound guidance and a contrast-enhanced, 64-slice multidetector CT scan was collected with the clips in place. Each clip was segmented from the CT scan at each of the five phases of the cardiac cycle at both end-inspiration and end-expiration. The centroid of each segmented clip was computed and used to evaluate both cardiac and respiratory motion of the left atrium. A total of three canine studies were completed, with 4 clips analyzed in the first study, 5 clips in the second study, and 2 clips in the third study. Mean respiratory displacement was 0.2±1.8 mm in the medial/lateral direction, 4.7±4.4 mm in the anterior/posterior direction (moving anterior on inspiration), and 9.0±5.0 mm superior/inferior (moving inferior with inspiration). At end inspiration, the mean left atrial cardiac motion at the clip locations was 1.5±1.3 mm in the medial/lateral direction, and 2.1±2.0 mm in the anterior/posterior and 1.3±1.2 mm superior/inferior directions. At end expiration, the mean left atrial cardiac motion at the clip locations was 2.0±1.5 mm in the medial/lateral direction, 3.0±1.8 mm in the anterior/posterior direction, and 1.5±1.5 mm in the superior/inferior directions.

Toward Standardized Mapping for Left Atrial Analysis and Cardiac Ablation Guidance.

In catheter-based cardiac ablation, the pulmonary vein ostia are important landmarks for guiding the ablation procedure, and for this reason, have been the focus of many studies quantifying their size, structure, and variability. Analysis of pulmonary vein structure, however, has been limited by the lack of a standardized reference space for population based studies. Standardized maps are important tools for characterizing anatomic variability across subjects with the goal of separating normal inter-subject variability from abnormal variability associated with disease. In this work, we describe a novel technique for computing flat maps of left atrial anatomy in a standardized space. A flat map of left atrial anatomy is created by casting a single ray through the volume and systematically rotating the camera viewpoint to obtain the entire field of view. The technique is validated by assessing preservation of relative surface areas and distances between the original 3D geometry and the flat map geometry. The proposed methodology is demonstrated on 10 subjects which are subsequently combined to form a probabilistic map of anatomic location for each of the pulmonary vein ostia and the boundary of the left atrial appendage. The probabilistic map demonstrates that the location of the inferior ostia have higher variability than the superior ostia and the variability of the left atrial appendage is similar to the superior pulmonary veins. This technique could also have potential application in mapping electrophysiology data, radio-frequency ablation burns, or treatment planning in cardiac ablation therapy.

Augmented environments for minimally invasive therapy: implementation barriers from technology to practice.

Augmented environments for medical applications have been explored and developed in an effort to enhance the clinician's view of anatomy and facilitate the performance of minimally invasive procedures. These environments must faithfully represent the real surgical field and require seamless integration of pre- and intra-operative imaging, surgical instrument tracking and display technology into a common framework centered around the patient. However, few image guidance environments have been successfully translated into clinical use. Several challenges that contribute to the slow progress of integrating such environments into clinical practice are discussed here in terms of both technical and clinical limitations.

Relationship of femoral neck areal bone mineral density to volumetric bone mineral density, bone size, and femoral strength in men and women.

UNLABELLED: Using combined dual-energy X-ray absorptiometry (DXA) and quantitative computed tomography, we demonstrate that men matched with women for femoral neck (FN) areal bone mineral density (aBMD) have lower volumetric BMD (vBMD), higher bone cross-sectional area, and relatively similar values for finite element (FE)-derived bone strength. INTRODUCTION: aBMD by DXA is widely used to identify patients at risk for osteoporotic fractures. aBMD is influenced by bone size (i.e., matched for vBMD, larger bones have higher aBMD), and increasing evidence indicates that absolute aBMD predicts a similar risk of fracture in men and women. Thus, we sought to define the relationships between FN aBMD (assessed by DXA) and vBMD, bone size, and FE-derived femoral strength obtained from quantitative computed tomography scans in men versus women. METHODS: We studied men and women aged 40 to 90 years and not on osteoporosis medications. RESULTS: In 114 men and 114 women matched for FN aBMD, FN total cross-sectional area was 38% higher (P < 0.0001) and vBMD was 16% lower (P < 0.0001) in the men. FE models constructed in a subset of 28 women and 28 men matched for FN aBMD showed relatively similar values for bone strength and the load-to-strength ratio in the two groups. CONCLUSIONS: In this cohort of young and old men and women from Rochester, MN, USA who are matched by FN aBMD, because of the offsetting effects of bone size and vBMD, femoral strength and the load-to-strength ratio tended to be relatively similar across the sexes.

A novel population of myeloid cells responding to coxsackievirus infection assists in the dissemination of virus within the neonatal CNS.

Enterovirus infection in newborn infants is a significant cause of aseptic meningitis and encephalitis. Using a neonatal mouse model, we previously determined that coxsackievirus B3 (CVB3) preferentially targets proliferating neural stem cells located in the subventricular zone within 24 h after infection. At later time points, immature neuroblasts, and eventually mature neurons, were infected as determined by expression of high levels of viral protein. Here, we show that blood-derived Mac3(+) mononuclear cells were rapidly recruited to the CNS within 12 h after intracranial infection with CVB3. These cells displayed a myeloid-like morphology, were of a peripheral origin based on green fluorescent protein (GFP)-tagged adoptive cell transplant examination, and were highly susceptible to CVB3 infection during their migration into the CNS. Serial immunofluorescence images suggested that the myeloid cells enter the CNS via the choroid plexus, and that they may be infected during their extravasation and passage through the choroid plexus epithelium; these infected myeloid cells ultimately penetrate into the parenchyma of the brain. Before their migration through the ependymal cell layer, a subset of these infected myeloid cells expressed detectable levels of nestin, a marker for neural stem and progenitor cells. As these nestin(+) myeloid cells infected with CVB3 migrated through the ependymal cell layer, they revealed distinct morphological characteristics typical of type B neural stem cells. The recruitment of these novel myeloid cells may be specifically set in motion by the induction of a unique chemokine profile in the CNS induced very early after CVB3 infection, which includes upregulation of CCL12. We propose that intracranial CVB3 infection may lead to the recruitment of nestin(+) myeloid cells into the CNS which might represent an intrinsic host CNS repair response. In turn, the proliferative and metabolic status of recruited myeloid cells may render them attractive targets for CVB3 infection. Moreover, the migratory ability of these myeloid cells may point to a productive method of virus dissemination within the CNS.

Lymph node-targeted immunotherapy mediates potent immunity resulting in regression of isolated or metastatic human papillomavirus-transformed tumors.

PURPOSE: The goal of this study was to investigate the therapeutic potential of a novel immunotherapy strategy resulting in immunity to localized or metastatic human papillomavirus 16-transformed murine tumors. EXPERIMENTAL DESIGN: Animals bearing E7-expressing tumors were coimmunized by lymph node injection with E7 49-57 antigen and TLR3-ligand (synthetic dsRNA). Immune responses were measured by flow cytometry and antitumor efficacy was evaluated by tumor size and survival. In situ cytotoxicity assays and identification of tumor-infiltrating lymphocytes and T regulatory cells were used to assess the mechanisms of treatment resistance in bulky disease. Chemotherapy with cyclophosphamide was explored to augment immunotherapy in late-stage disease. RESULTS: In therapeutic and prophylactic settings, immunization resulted in a considerable expansion of E7 49-57 antigen-specific T lymphocytes in the range of 1/10 CD8(+) T cells. The resulting immunity was effective in suppressing disease progression and mortality in a pulmonary metastatic disease model. Therapeutic immunization resulted in control of isolated tumors up to a certain volume, and correlated with antitumor immune responses measured in blood. In situ analysis showed that within bulky tumors, T-cell function was affected by negative regulatory mechanisms linked to an increase in T regulatory cells and could be overcome by cyclophosphamide treatment in conjunction with immunization. CONCLUSIONS: This study highlights a novel cancer immunotherapy platform with potential for translatability to the clinic and suggests its potential usefulness for controlling metastatic disease, solid tumors of limited size, or larger tumors when combined with cytotoxic agents that reduce the number of tumor-infiltrating T regulatory cells.

TLR-9 signaling and TCR stimulation co-regulate CD8(+) T cell-associated PD-1 expression.

Elevated Programmed Death-1 (PD-1) expression can inhibit T cell activity and is a potential barrier to achieving persisting and optimal immunity via therapeutic vaccination. Using a direct lymph node-targeted vaccination procedure that enabled uncoupling of synthetic peptide (signal 1, TCR-mediated) and adjuvant (signal 2, non-TCR-mediated), we evaluated the impact of varied doses of Toll-like receptor (TLR)-9 ligand CpG oligodeoxynucleotide (ODN) adjuvant on epitope-specific CD8(+) T cell-associated PD-1 expression. Peptide vaccination without adjuvant yielded CD8(+) T cells with significantly elevated PD-1 expression. This conferred impaired function ex vivo, but was reversible by antibody-mediated PD-1 blockade. By comparison, peptide vaccination with escalating doses of CpG ODN adjuvant yielded higher magnitudes of CD8(+) T cells with progressively lower PD-1 expression and greater ex vivo function. CpG ODN adjuvant in context of titrated peptide doses for vaccination yielded the lowest overall PD-1 expression levels, demonstrating that fine-tuning both TCR-independent (adjuvant dose) and -dependent (antigen dose) stimuli can synergize to co-regulate PD-1 expression on epitope-specific CD8(+) T cells. These data hint at strategies to elicit PD-1(low) CD8(+) T cells using TLR-9 ligand adjuvants, and also shed light on the PD-1-regulated homeostasis of CD8(+) T cells.

Viral persistence and chronic immunopathology in the adult central nervous system following Coxsackievirus infection during the neonatal period.

Coxsackieviruses are significant human pathogens, and the neonatal central nervous system (CNS) is a major target for infection. Despite the extreme susceptibility of newborn infants to coxsackievirus infection and viral tropism for the CNS, few studies have been aimed at determining the long-term consequences of infection on the developing CNS. We previously described a neonatal mouse model of coxsackievirus B3 (CVB3) infection and determined that proliferating stem cells in the CNS were preferentially targeted. Here, we describe later stages of infection, the ensuing inflammatory response, and subsequent lesions which remain in the adult CNS of surviving animals. High levels of type I interferons and chemokines (in particular MCP-5, IP10, and RANTES) were upregulated following infection and remained at high levels up to day 10 postinfection (p.i). Chronic inflammation and lesions were observed in the hippocampus and cortex of surviving mice for up to 9 months p.i. CVB3 RNA was detected in the CNS up to 3 months p.i at high abundance ( approximately 10(6) genomes/mouse brain), and viral genomic material remained detectable in culture after two rounds of in vitro passage. These data suggest that CVB3 may persist in the CNS as a low-level, noncytolytic infection, causing ongoing inflammatory lesions. Thus, the effects of a relatively common infection during the neonatal period may be long lasting, and the prognosis for newborn infants recovering from acute infection should be reexplored.

Enhancing DNA vaccination by sequential injection of lymph nodes with plasmid vectors and peptides.

DNA vaccines or peptides are capable of inducing specific immunity; however, their translation to the clinic has generally been problematic, primarily due to the reduced magnitude of immune response and poor pharmacokinetics. Herein, we demonstrate that a novel immunization strategy, encompassing sequential exposure of the lymph node milieu to plasmid and peptide in a heterologous prime-boost fashion, results in considerable MHC class I-restricted immunity in mice. Plasmid-primed antigen expression was essential for the generation of a population of central memory T cells, expressing CD62L and low in PD-1, with substantial capability to expand and differentiate to peripheral memory and effector cells, following subsequent exposure to peptide. These vaccine-induced T cells dominated the T cell repertoire, were able to produce large amounts of chemokines and pro-inflammatory cytokines, and recognized tumor cells effectively. In addition to outlining a feasible and effective method to transform plasmid DNA vaccination into a potentially viable immunotherapeutic approach for cancer, this study sheds light on the mechanism of heterologous prime-boost and the considerable heterogeneity of MHC class I-restricted T cell responses.

An event-driven distributed processing architecture for image-guided cardiac ablation therapy.

Medical imaging data is becoming increasing valuable in interventional medicine, not only for preoperative planning, but also for real-time guidance during clinical procedures. Three key components necessary for image-guided intervention are real-time tracking of the surgical instrument, aligning the real-world patient space with image-space, and creating a meaningful display that integrates the tracked instrument and patient data. Issues to consider when developing image-guided intervention systems include the communication scheme, the ability to distribute CPU intensive tasks, and flexibility to allow for new technologies. In this work, we have designed a communication architecture for use in image-guided catheter ablation therapy. Communication between the system components is through a database which contains an event queue and auxiliary data tables. The communication scheme is unique in that each system component is responsible for querying and responding to relevant events from the centralized database queue. An advantage of the architecture is the flexibility to add new system components without affecting existing software code. In addition, the architecture is intrinsically distributed, in that components can run on different CPU boxes, and even different operating systems. We refer to this Framework for Image-Guided Navigation using a Distributed Event-Driven Database in Real-Time as the FINDER architecture. This architecture has been implemented for the specific application of image-guided cardiac ablation therapy. We describe our prototype image-guidance system and demonstrate its functionality by emulating a cardiac ablation procedure with a patient-specific phantom. The proposed architecture, designed to be modular, flexible, and intuitive, is a key step towards our goal of developing a complete system for visualization and targeting in image-guided cardiac ablation procedures.

Application of magnetic resonance imaging to measure fasting and postprandial volumes in humans.

Our aims were to measure the gastric volume response in excess of ingested meal volume (i.e. gastric accommodation), contribution of swallowed air to this excess, day-to-day variability of gastric volumes measured by MRI and their relationship to volumes measured by single-photon-emission computed tomography (SPECT). In 20 healthy volunteers, fasting and postprandial gastric volumes were measured after technetium(99m)-pertechnetate labeling of the gastric mucosa by SPECT and separately by MRI, using 3D gradient echo and 2D half-Fourier acquisition single-shot turbo spin echo (HASTE) sequences. Ten of these subjects had a second MRI exam to assess intra-individual variation. Thereafter, another 10 subjects had two MRI studies during which they ingested the nutrient in 30 or 150 mL aliquots. During MRI, the postprandial gastric volume change exceeded the ingested meal volume by 106 +/- 12 mL (Mean +/- SEM). The HASTE and gradient echo sequences distinguished air from fluid under fasting and postprandial conditions respectively. This postprandial excess mainly comprised air (61 +/- 5 mL), which was not significantly different when ingested as 30 or 150 mL aliquots. Fasting and postprandial gastric volumes measured by MRI were generally reproducible within subjects. During SPECT, postprandial volumes increased by 158 +/- 18 mL; gastric volumes measured by SPECT were higher than MRI. MRI measures gastric volumes with acceptable performance characteristics; the postprandial excess primarily consists of air, which is not affected by the mode of ingestion. Gastric volumes are technique specific and differ between MRI and SPECT.

Patient specific physical anatomy models.

The advent of small footprint stereo-lithographic printers and the ready availability of segmentation and surface modeling software provide a unique opportunity to create patient-specific physical models of anatomy, validation of image guided intervention applications against phantoms that exhibit naturally occurring anatomic variation. Because these models can incorporate all structures relevant to a procedure, this allows validation to occur under realistic conditions using the same or similar techniques as would be used in a clinical application. This in turn reduces the number of trials and time spent performing in-vivo validation experiments. In this paper, we describe our general approach for the creation of both non-tissue and tissue-mimicking patient-specific models as part of a general-purpose patient emulation system used to validate image guided intervention applications.

Acute cholecystitis.

INTRODUCTION: Of people admitted to hospital for biliary tract disease, 20% have acute cholecystitis. Up to the age of 50 years, acute calculous cholecystitis is three times more common in women than in men, and about 1.5 times more common in women than in men thereafter. About 95% of people with acute cholecystitis have gallstones. Optimal therapy for acute cholecystitis, based on timing and severity of presentation, remains controversial. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for acute cholecystitis? We searched: Medline, Embase, The Cochrane Library, and other important databases up to December 2006 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 12 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: early cholecystectomy, laparoscopic cholecystectomy, minilaparoscopic cholecystectomy, observation alone, and open cholecystectomy.

Telemedicine process used to implement an effective and functional screening program for diabetic retinopathy.

BACKGROUND: Diabetic retinopathy, damage to the blood vessels in the retina, is the leading cause of blindness in adults 20-74 years of age. Nearly 300 million people worldwide have diabetes and nearly half of all people with diabetes will develop some degree of diabetic retinopathy during their lifetime. It has been estimated that blindness from diabetic retinopathy is preventable in at least 65% of cases, if detected early. The aim of the project was to develop a flexible, modular, mobile method for screening individuals that could be used effectively in a variety of medical and community settings. METHODS: Our project created software to support a simple, effective retinal screening process for people with diabetes. The system included four separate software components: registration, imaging, grading, and tracking/reporting. The imaging component consisted of customized software running on a computer attached to a camera that drives retinal image acquisition. RESULTS: Seven hundred and six subjects with diabetes were successfully consented, registered, imaged, and had their eye images graded. The mean time for subjects to be registered, imaged, and have eye images graded was 00:12:53. Seventy-six percent of the sample was instructed to follow-up with their eye doctor in 1 year (had no retinopathy or microaneurysms). Only six patients (0.8 %) were asked to see their eye doctor within 6 weeks (proliferative retinopathy or diabetic maculopathy). CONCLUSION: Our project successfully demonstrated that the retinal screening software and workflow process can be used to overcome challenges of providing adequate screening and diagnostic services for people at risk for diabetic retinopathy.

An integrated system for real-time image guided cardiac catheter ablation.

Minimally invasive cardiac catheter ablation procedures require effective visualization of the relevant heart anatomy and electrophysiology (EP). In a typical ablation procedure, the visualization tools available to the cardiologist include bi-plane fluoroscopy, real-time ultrasound, and a coarse 3D model which gives a rough representation of cardiac anatomy and electrical activity. Recently, there has been increased interest in incorporating detailed, patient specific anatomical data into the cardiac ablation procedure. We are currently developing a prototype system which both integrates a patient specific, preoperative data model into the procedure as well as fuses the various visualization modalities (i.e. fluoroscopy, ultrasound, EP) into a single display. In this paper, we focus on two aspects of the prototype system. First, we describe the framework for integrating the various system components, including an efficient communication protocol. Second, using a simple two-chamber phantom of the heart, we demonstrate the ability to integrate preoperative data into the ablation procedure. This involves the registration and visualization of tracked catheter points within the cardiac chambers of the preoperative model.

Quantitative characterization of lung disease.

The increase in prevalence, incidence and variety of pulmonary diseases has precipitated the need for more non-invasive quantitative assessment of structure/function relationships in the lung. This need requires concise description not only of lung anatomy but also of associated underlying mechanics of pulmonary function, as well as deviation from normal in specific diseases. This can be facilitated through the use of adaptive deformable surface models of the lung at end inspiratory and expiratory volumes. Lung surface deformation may be used to represent tissue excursion, which can characterize both global and regional lung mechanics. In this paper, we report a method for robust determination and visualization of pulmonary structure and function using clinical CT scans. The method provides both intuitive 3D parametric visualization and objective quantitative assessment of lung structure and associated function, in both normal and pathological cases.

Evaluation of the applicability, efficacy, and safety of a thromboembolic event prophylaxis guideline designed for quality improvement of the traumatically injured patient.

BACKGROUND: Thromboembolic events (TE) such as deep venous thrombosis (DVT) and pulmonary embolism (PE) are common after trauma. Our Trauma Practice Management Committee developed an evidence-based DVT/PE prophylaxis guideline using a modified Delphi approach to standardize care and reduce TE rates. Our objective was to evaluate the applicability, efficacy, and safety of this guideline in the traumatized patient, especially those admitted first to the intensive care unit (ICU). METHODS: We developed a risk-stratified DVT/PE prophylaxis guideline incorporating specific injuries, pertinent history, and physiologic parameters, favoring aggressive therapy in those at highest risk of dying from a PE. We prospectively collected data using this guideline in all patients admitted to the trauma or orthopedic-trauma services that were expected to stay for more than 48 hours (March-December 2003). Comparison was made with historical controls. Data collected included DVT, PE, prophylaxis level chosen, inferior vena cava filters, admission service and location, TRISS scores, length of stay, outcomes, adverse events, and specific risk factors. RESULTS: TE rates after implementation of the guideline were lower than historical controls for all patients (1.9% vs. 1.0%, p = 0.059) and for patients admitted first to the ICU (6.3% vs. 2%, p = 0.018). Completed sheets were collected for 46% of the targeted population. No bleeding events caused by guideline anticoagulation were noted, and one death occurred after inferior vena cava filter placement. Nine of the 12 TEs in the treatment group were in patients with spine or closed-head injury, delaying chemical prophylaxis. CONCLUSION: Form-based, risk-adjusted prophylaxis against TE leads to lower TE rates in a general and orthopedic ICU trauma population. Protocol compliance should be enforced.

Coxsackievirus targets proliferating neuronal progenitor cells in the neonatal CNS.

Type B coxsackieviruses (CVB) frequently infect the CNS and, together with other enteroviruses, are the most common cause of viral meningitis in humans. Newborn infants are particularly vulnerable, and CVB also can infect the fetus, leading to mortality, or to neurodevelopmental defects in surviving infants. Using a mouse model of neonatal CVB infection, we previously demonstrated that coxsackievirus B3 (CVB3) could infect neuronal progenitor cells in the subventricular zone (SVZ). Here we extend these findings, and we show that CVB3 targets actively proliferating (bromodeoxyuridine+, Ki67+) cells in the SVZ, including type B and type A stem cells. However, infected cells exiting the SVZ have lost their proliferative capacity, in contrast to their uninfected companions. Despite being proliferation deficient, the infected neuronal precursors could migrate along the rostral migratory stream and radial glia, to reach their final destinations in the olfactory bulb or cerebral cortex. Furthermore, infection did not prevent cell differentiation, as determined by cellular morphology and the expression of maturation markers. These data lead us to propose a model of CVB infection of the developing CNS, which may explain the neurodevelopmental defects that result from fetal infection.

Has control of hypercholesterolemia and hypertension in type 1 diabetes improved over time?

OBJECTIVE: To determine the extent to which patients' awareness, treatment, and control of hypertension and hypercholesterolemia have changed over time and to examine factors associated with awareness and treatment in a type 1 diabetes population. RESEARCH DESIGN AND METHODS: Data from six examinations conducted over 10 years from the Pittsburgh Epidemiology of Diabetes Complications Study, a prospective study of subjects with childhood-onset (<17 years of age) type 1 diabetes diagnosed between 1950 and 1980 and followed since 1986, were analyzed. Hypertension and hypercholesterolemia were defined according to the concurrent Joint National Committee and National Cholesterol Education Program Adult Treatment Panel criteria, respectively. RESULTS: Results demonstrated that awareness of both conditions has improved; however, control is not optimal (e.g., only 32.1 and 28% of those with hypertension in 1986-1988 and 1996-1998 were controlled, while for hypercholesterolemia, the rates were 0 and 5.5%, respectively). Stratified by age-group (18-29, 30-39, and >40 years), the youngest subjects with hypercholesterolemia were least likely to be treated and controlled to goal levels. Older age and physician contact were correlates of awareness and treatment of hypertension at baseline, while presence of renal or coronary complications was also associated with awareness and treatment of both hypertension and hypercholesterolemia at the 10-year follow-up. CONCLUSIONS: There is a considerable treatment gap, particularly for hypercholesterolemia. Improved treatment of both hypertension and hypercholesterolemia are clearly needed, particularly hypercholesterolemia in younger age-groups who have not yet experienced long-term complications.