VA Central California Health Care System

Diabetes is defined by its association with hyperglycemia-specific microvascular complications; however, it also imparts a two- to fourfold risk of cardiovascular disease (CVD). Although microvascular complications can lead to significant morbidity and premature mortality, by far the greatest cause of death in people with diabetes is CVD. Results from randomized controlled trials have demonstrated conclusively that the risk of microvascular complications can be reduced by intensive glycemic control in patients with type 1 (1,2) and type 2 diabetes (3–5). In the Diabetes Control and Complications Trial (DCCT), there was an ∼60% reduction in development or progression of diabetic retinopathy, nephropathy, and neuropathy between the intensively treated group (goal A1C <6.05%, mean achieved A1C ∼7%) and the standard group (A1C ∼9%) over an average of 6.5 years. The relationship between glucose control (as reflected by the mean on-study A1C value) and risk of complications was log-linear and extended down to the normal A1C range (<6%) with no threshold noted. In the UK Prospective Diabetes Study (UKPDS), participants newly diagnosed with type 2 diabetes were followed for 10 years, and intensive control (median A1C 7.0%) was found to reduce the overall microvascular complication rate by 25% compared with conventional treatment (median A1C 7.9%). Here, too, secondary analyses showed a continuous relationship between the risk of microvascular complications and glycemia extending into the normal range of A1C, with no glycemic threshold. On the basis of these two large controlled trials, along with smaller studies and numerous epidemiologic reports, the consistent findings related to microvascular risk reduction with intensive glycemic control have led the American Diabetes Association (ADA) to recommend an A1C goal of <7% for most adults with diabetes (6), recognizing that more or less stringent goals may be appropriate for certain patients. Whereas many epidemiologic studies and meta-analyses …

CONTEXT: The Centers for Disease Control and Prevention estimates that approximately 1.4 million US individuals sustain traumatic brain injuries (TBIs) per year. Previous reports suggest an association between TBI and chronic pain syndromes (eg, headache) thought to be more common in patients with mild TBI and in those who have sustained brain injury from violent rather than unintentional trauma. Comorbid psychiatric disorders such as posttraumatic stress disorder (PTSD) may also mediate chronic pain symptoms. OBJECTIVES: To determine the prevalence of chronic pain as an underdiagnosed consequence of TBI and to review the interaction between chronic pain and severity of TBI as well as the characteristics of pain after TBI among civilians and combatants. EVIDENCE ACQUISITION: The Ovid/MEDLINE database was searched for articles published between 1951 and February 2008 using any combination of the terms brain injury, pain, headache, blast injury, and combat (combat disorders, war, military medicine, wounds and injuries, military personnel, veterans). The PubMed and MD Consult databases were searched in a similar fashion. The Cochrane Collaboration, National Institutes of Health Clinical Trials Database, Meta-Register of Current Controlled Trials, and CRISP databases were searched using the keyword brain injury. All articles in peer-reviewed journals reporting original data on pain syndromes in adult patients with TBI with regard to pain prevalence, pain category, risk factors, pathogenesis, and clinical course were selected, and manual searches were performed of their reference lists. The data were pooled and prevalence rates calculated. EVIDENCE SYNTHESIS: Twenty-three studies (15 cross-sectional, 5 prospective, and 3 retrospective) including 4206 patients were identified. Twelve studies assessed headache pain in 1670 patients. Of these, 966 complained of chronic headache, yielding a prevalence of 57.8% (95% confidence interval [CI], 55.5%-60.2%). Among civilians, the prevalence of chronic pain was greater in patients with mild TBI (75.3% [95% CI, 72.7%-77.9%]) compared with moderate or severe TBI (32.1% [95% CI, 29.3%-34.9%]). Twenty studies including 3289 civilian patients with TBI yielded a chronic pain prevalence of 51.5% (95% CI, 49.8%-53.2%). Three studies assessed TBI among 917 veterans and yielded a pain prevalence of 43.1% (95% CI, 39.9%-46.3%). PTSD may mediate chronic pain, but brain injury appears to have an independent correlation with chronic pain. CONCLUSIONS: Chronic pain is a common complication of TBI. It is independent of psychologic disorders such as PTSD and depression and is common even among patients with apparently minor injuries to the brain.

The COVID-19 pandemic has altered mental health care delivery like no other event in modern history. The purpose of this study was to document the magnitude of that effect by examining (a) the amount of psychologists' telepsychology use before the COVID-19 pandemic, during the pandemic, and anticipated use after the pandemic; as well as (b) the demographic, training, policy, and clinical practice predictors of these changes. This study used a cross-sectional, national online design to recruit 2,619 licensed psychologists practicing in the United States. Prior to the COVID-19 pandemic, psychologists performed 7.07% of their clinical work with telepsychology, which increased 12-fold to 85.53% during the pandemic, with 67.32% of psychologists conducting all of their clinical work with telepsychology. Psychologists projected that they would perform 34.96% of their clinical work via telepsychology after the pandemic. Psychologists working in outpatient treatment facilities reported over a 26-fold increase in telepsychology use during the pandemic, while those in Veterans Affairs medical centers only reported a sevenfold increase. A larger increase in percentage telepsychology use occurred in women, in psychologists who reported an increase in telepsychology training and supportive organizational telepsychology policies, and in psychologists who treated relationship issues, anxiety, and women's issues. The lowest increases in percentage telepsychology use were reported by psychologists working in rural areas, treating antisocial personality disorder, performing testing and evaluation, and treating rehabilitation populations. Although there was a remarkable increase in telepsychology use during the COVID-19 pandemic, individual and practice characteristics affected psychologists' ability to adopt telepsychology. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Metastatic prostate cancer (mPC) comprises a spectrum of diverse phenotypes. However, the extent of inter- and intra-tumor heterogeneity is not established. Here we use digital spatial profiling (DSP) technology to quantitate transcript and protein abundance in spatially-distinct regions of mPCs. By assessing multiple discrete areas across multiple metastases, we find a high level of intra-patient homogeneity with respect to tumor phenotype. However, there are notable exceptions including tumors comprised of regions with high and low androgen receptor (AR) and neuroendocrine activity. While the vast majority of metastases examined are devoid of significant inflammatory infiltrates and lack PD1, PD-L1 and CTLA4, the B7-H3/CD276 immune checkpoint protein is highly expressed, particularly in mPCs with high AR activity. Our results demonstrate the utility of DSP for accurately classifying tumor phenotype, assessing tumor heterogeneity, and identifying aspects of tumor biology involving the immunological composition of metastases.

Although magnesium is involved in a wide spectrum of vital functions in normal human physiology, the significance of hypomagnesemia and necessity for its treatment are under-recognized and underappreciated in clinical practice. In the current review, we first present an overview of the clinical significance of hypomagnesemia and normal magnesium metabolism, with a focus on renal magnesium handling. Subsequently, we review the literature for both congenital and acquired hypomagnesemic conditions that affect the various steps in normal magnesium metabolism. Finally, we present an approach to the routine evaluation and suggested management of hypomagnesemia.

Importance: Posttraumatic stress disorder (PTSD) is a prevalent and serious mental health problem. Although there are effective psychotherapies for PTSD, there is little information about their comparative effectiveness. Objective: To compare the effectiveness of prolonged exposure (PE) vs cognitive processing therapy (CPT) for treating PTSD in veterans. Design, Setting, and Participants: This randomized clinical trial assessed the comparative effectiveness of PE vs CPT among veterans with military-related PTSD recruited from outpatient mental health clinics at 17 Department of Veterans Affairs medical centers across the US from October 31, 2014, to February 1, 2018, with follow-up through February 1, 2019. The primary outcome was assessed using centralized masking. Tested hypotheses were prespecified before trial initiation. Data were analyzed from October 5, 2020, to May 5, 2021. Interventions: Participants were randomized to 1 of 2 individual cognitive-behavioral therapies, PE or CPT, delivered according to a flexible protocol of 10 to 14 sessions. Main Outcomes and Measures: The primary outcome was change in PTSD symptom severity on the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) from before treatment to the mean after treatment across posttreatment and 3- and 6-month follow-ups. Secondary outcomes included other symptoms, functioning, and quality of life. Results: Analyses were based on all 916 randomized participants (730 [79.7%] men and 186 [20.3%] women; mean [range] age 45.2 [21-80] years), with 455 participants randomized to PE (mean CAPS-5 score at baseline, 39.9 [95% CI, 39.1-40.7] points) and 461 participants randomized to CPT (mean CAPS-5 score at baseline, 40.3 [95% CI, 39.5-41.1] points). PTSD severity on the CAPS-5 improved substantially in both PE (standardized mean difference [SMD], 0.99 [95% CI, 0.89-1.08]) and CPT (SMD, 0.71 [95% CI, 0.61-0.80]) groups from before to after treatment. Mean improvement was greater in PE than CPT (least square mean, 2.42 [95% CI, 0.53-4.31]; P = .01), but the difference was not clinically significant (SMD, 0.17). Results for self-reported PTSD symptoms were comparable with CAPS-5 findings. The PE group had higher odds of response (odds ratio [OR], 1.32 [95% CI, 1.00-1.65]; P < .001), loss of diagnosis (OR, 1.43 [95% CI, 1.12-1.74]; P < .001), and remission (OR, 1.62 [95% CI, 1.24-2.00]; P < .001) compared with the CPT group. Groups did not differ on other outcomes. Treatment dropout was higher in PE (254 participants [55.8%]) than in CPT (215 participants [46.6%]; P < .01). Three participants in the PE group and 1 participant in the CPT group were withdrawn from treatment, and 3 participants in each treatment dropped out owing to serious adverse events. Conclusions and Relevance: This randomized clinical trial found that although PE was statistically more effective than CPT, the difference was not clinically significant, and improvements in PTSD were meaningful in both treatment groups. These findings highlight the importance of shared decision-making to help patients understand the evidence and select their preferred treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT01928732.

Cirrhosis of liver is a major problem in the western world. Portal hypertension is a complication of cirrhosis and can lead to a myriad of pathology of which include the development of porto-systemic collaterals. Gastrointestinal varices are dilated submucosal veins, which often develop at sites near the formation of gastroesophageal collateral circulation. The incidence of varices is on the rise due to alcohol and obesity. The most significant complication of portal hypertension is life-threatening bleeding from gastrointestinal varices, which is associated with substantial morbidity and mortality. In addition, this can cause a significant burden on the health care facility. Gastrointestinal varices can happen in esophagus, stomach or ectopic varices. There has been considerable progress made in the understanding of the natural history, pathophysiology and etiology of portal hypertension. Despite the development of endoscopic and medical treatments, early mortality due to variceal bleeding remains high due to significant illness of the patient. Recurrent variceal bleed is common and in some cases, there is refractory variceal bleed. This article aims to provide a comprehensive review of the management of gastrointestinal varices with an emphasis on endoscopic interventions, strategies to handle refractory variceal bleed and newer endoscopic treatment modalities. Early treatment and improved endoscopic techniques can help in improving morbidity and mortality.

BACKGROUND: Exercise microvolt T-wave alternans (TWA) identifies sudden cardiac death (SCD) risk. TWA can be measured from ambulatory ECGs (AECGs) using modified moving average (MMA) method. Whether MMA TWA from AECGs predicts SCD in post-MI patients with left ventricular dysfunction (LVD) is unknown. METHODS: EPHESUS enrolled hospitalized post-MI patients with heart failure and/or diabetes with LVD. Before randomization to drug treatment, AECGs were obtained in 493 patients. Of them, 46 died of cardiovascular causes, including 18 of SCD. Patients alive at end of follow-up (N = 92) were matched with 46 nonsurvivors based on age, gender, and diabetes. MMA TWA was analyzed using MARSPC system (GE Healthcare, Milwaukee, WI, USA). The three highest TWA values from artifact-free periods were averaged for AECG channels corresponding to leads V(1) and V(3). SCD prediction was tested with a prespecified 47 microV cutpoint and at a cutpoint maximizing the separation between SCD patients versus survivors or non-SCD. RESULTS: TWA in either lead was higher for patients with SCD (P < or = 0.05) versus survivors or non-SCD. TWA > or = 47 microV was associated with RR = 5.2 (95%CI = 1.8-13.6, P = 0.002) in V(1) and RR = 5.5 (95% CI = 2.2-13.8, P < 0.001) in V(3) for SCD. The optimal cutpoint for TWA in V(1) was > or = 43 microV (RR = 5.9 [95%CI = 2.2-15.8, P < 0.001]). The optimal cutpoint in V(3) was > or = 47 microV. TWA greater than the optimal cutpoint in either lead was associated with RR = 7.1 (95%CI = 2.7-18.3, P < 0.001) for SCD, with 11 out of 18 patients dying of SCD. CONCLUSIONS: AECG-based TWA measured with MMA is a powerful predictor of SCD in high-risk post-MI patients with LV dysfunction.

Hypertension frequently coexists with diabetes and the cardiometabolic syndrome. β-Blockers have been a mainstay for controlling blood pressure for nearly 4 decades. However, β-blockers are perceived to cause glucose and lipid metabolism dysregulation, including hypoglycemia masking, reduced glycemic control, insulin resistance, and dyslipidemia. It should be noted, however, that β-blockers are diverse in their effects on glucose and lipid metabolism. Potential mechanisms that contribute to these metabolic effects include hemodynamic differences, anti-inflammatory and anti-oxidative pathways, and/or weight changes. Traditional β-blockers decrease cardiac output while peripheral vascular resistance increases or remains unchanged, which may result in glucose and lipid abnormalities. In contrast, vasodilating β-blockers reduce peripheral vascular resistance but have little effect on cardiac output. Vasodilating β-blockers may therefore result in less impact on insulin sensitivity and glycemic control, a reduced new-onset diabetes risk, and improved dyslipidemia compared with traditional β-blockers. Because of these effects, vasodilating β-blockers may represent a favorable option in the treatment of high-risk patients with hypertension.

Cardiovascular disease (CVD) remains the top cause of global mortality. There is considerable evidence that supports the mortality and morbidity benefit of statin therapy in coronary heart disease (CHD) and stroke, both in primary and secondary prevention settings. Data also exist pointing to the advantage of statin treatment in other high-risk CVD conditions, such as diabetes, CKD, CHF, and PVD. National and international clinical guidelines in the management of these CVD conditions all advocate for the utilization of statin therapy in appropriate patients. However, overall compliance to statin therapy remains suboptimal. Patient-, physician-, and economic-related factors all play a role. These factors need to be considered in devising approaches to enhance adherence to guideline-based therapies. To fully reap the benefits of statin therapy, interventions which improve long-term treatment compliance in real-world settings should be encouraged.

BACKGROUND: The purpose of this study was to evaluate a telemedicine model that utilizes an audiovisual teleconference as a preoperative visit. METHODS: Veterans Health Administration (VHA) patients with head and neck cancer at 2 remote locations were provided access to the Palo Alto Veterans Affairs (PAVA) Health Care System otolaryngology department via the telemedicine protocol: tissue diagnosis and imaging at the patient site; data review at PAVA; and a preoperative teleconference connecting the patient to PAVA. Operative care occurred at PAVA. Follow-up care was provided remotely via teleconference. RESULTS: Fifteen patients were evaluated. Eleven underwent surgery, 4 with high-grade neoplasms (carcinoma). Average time from referral to operation was 28 days (range, 17-36 days) and 72 (range, 31-108 days), respectively, for high-grade and low-grade groups. The average patient was spared 28 hours traveling time and $900/patient was saved on travel-related costs. CONCLUSION: A telemedicine model enables timely access to surgical care and permits considerable savings among select VHA patients with head and neck cancer. © 2016 Wiley Periodicals, Inc. Head Neck 38: 925-929, 2016.

We analyzed data from 10 young infants who received exchange blood transfusions for management of severe pertussis. Our data are insufficient to address efficacy of the procedure, but our data, as well as previous reports in the literature, indicate that if the procedure is to be successful, it should be done before organ failure has occurred and immediately if shock/hypotension occur.

BACKGROUND AND AIMS: Patients develop breakthrough COVID-19 infection despite vaccination. The aim of this study was to identify outcomes in patients with cirrhosis who developed postvaccination COVID-19. METHODS: We performed a retrospective cohort study among US veterans with cirrhosis and postvaccination or unvaccinated COVID-19. Patients were considered fully vaccinated if COVID-19 was diagnosed 14 days after the second dose of either the Pfizer BNT162b2, the Moderna 1273-mRNA, or the single-dose Janssen Ad.26.COV2.S vaccines and partially vaccinated if COVID-19 was diagnosed 7 days after the first dose of any vaccine but prior to full vaccination. We investigated the association of postvaccination COVID-19 with mortality. RESULTS: We identified 3242 unvaccinated and 254 postvaccination COVID-19 patients with cirrhosis (82 after full and 172 after partial vaccination). In a multivariable analysis of a 1:2 propensity-matched cohort including vaccinated (n = 254) and unvaccinated (n = 508) participants, postvaccination COVID-19 was associated with reduced risk of death (adjusted HR [aHR], 0.21; 95% CI, 0.11-0.42). The reduction was observed after both full (aHR, 0.22; 95% CI, 0.08-0.63) and partial (aHR, 0.19; 95% CI, 0.07-0.54) vaccination, following the 1273-mRNA (aHR, 0.12; 95% CI 0.04-0.37) and BNT162b2 (aHR, 0.27; 95% CI, 0.10-0.71) vaccines and among patients with compensated (aHR, 0.19; 95% CI, 0.08-0.45) and decompensated (aHR, 0.27; 95% CI, 0.08-0.90) cirrhosis. Findings were consistent in a sensitivity analysis restricted to participants who developed COVID-19 after vaccine availability. CONCLUSIONS: Though patients with cirrhosis can develop breakthrough COVID-19 after full or partial vaccination, these infections are associated with reduced mortality.

The treatment of high-risk hypertensive patients with diabetes presents clinicians with challenges and opportunities. The coexistence of hypertension and diabetes dramatically and synergistically increases the risk of microvascular and macrovascular complications. Perhaps most important among these is the increased risk of cardiovascular events in this patient population, an observation that can be best appreciated by the increased number of deaths attributed to cardiovascular-related diseases in diabetic patients aged 45 to 65 years. Consequently, aggressive therapy in this population offers the promise of significantly reducing excess cardiovascular deaths. Despite this opportunity for reducing mortality in these high-risk patients, several challenges to treatment remain. While aggressive blood pressure reduction has been documented to reduce the rate of events in these patients, questions remain as to the level to which blood pressure should be reduced. The recent guidelines from the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure emphasized the importance of treating patients with hypertension and diabetes as if they already have target organ damage. Low blood pressure targets of 130/85 mm Hg, with an optimal goal of 120/80 mm Hg, can reduce the risk of events in hypertensive patients with diabetes, regardless of the pharmacological means used. However, there are physiologic and clinical rationale for renin angiotensin system blockade, with angiotensin-converting enzyme inhibition as the preferential therapy in these patients. In this regard, preliminary data with the new class of angiotensin II receptor blockers suggest that these agents may offer benefits equivalent to those observed with angiotensin-converting enzyme inhibitors while offering better tolerance.

Autosomal recessively inherited mutations in WNT1 were recently identified as a cause of severe osteogenesis imperfecta (OI).1–6 This finding does not address the critical role of Wnt1 in mid-hindbrain development that is well described in model organisms.7 ,8 Severe intellectual and motor deficits were noted in 4 of 16 families reported to date, but few details were provided. We reviewed developmental outcomes and brain-imaging studies for one new and five previously reported individuals with WNT1-associated OI. All six have brain malformations, with prominent brainstem and cerebellar hypoplasia in five of these six individuals. Homozygous or compound heterozygous mutations in WNT1 were recently described as a novel cause for severe autosomal-recessive OI in 25 individuals from 16 families in a series of six papers.1–6 Brain-imaging studies in two individuals were reported to show unilateral cerebellar hypoplasia,2 ,4 and another was reported to have Chiari malformation type 1.5 However, only limited data were presented regarding the brain and neurological phenotypes, including only a single MRI image. This is an important issue to address, as the WNT family of secreted signalling proteins play key roles in many developmental and homeostatic processes.9 Indeed, prominent defects in early brain development were described in two mouse lines with Wnt1 mutations long before WNT1 mutations were identified as a cause of bone fragility in humans.7 ,8 To examine the human brain phenotype associated with mutations in WNT1 , we reviewed all available brain-imaging studies from one new and five previously reported individuals including one sibling pair,1–5 which consisted of five brain MRI (figure 1) and one cranial CT scan (see online supplementary figure S1). We found significant malformations in all six individuals (table 1). Hippocampal malformations were found in three affected individuals for whom coronal MRI …

OBJECTIVE: Corticosteroids generally result in short-lasting neuropsychiatric symptoms following cessation, but the following case highlights an unusually long-lasting course of symptoms in a patient following near immediate cessation of medication, despite medication management and electroconvulsive therapy. The case presentation will be followed by a discussion of the presentation, treatment, and management of steroid-induced neuropsychiatric symptoms. METHODS: The patient was followed from symptom onset to resolution. RESULTS: The patient's symptom course was unusually long and required a long course of multimodal therapy. CONCLUSIONS: Corticosteroids are commonly used medications both in a wide variety of medical settings, and despite this, their neuropsychiatric effects are poorly understood. The affective and behavioral symptoms, in particular mania and psychosis, can be unpredictable and challenging to treat as in our patient, who developed a long-lasting psychotic episode on high-dose steroids despite discontinuation and treatment of nearly six months. This was despite having tolerated steroids multiple times in the past.

Congestive heart failure is a complex clinical hemodynamic disorder characterized by chronic and progressive pump failure and fluid accumulation. Although the overall impact of diuretic therapy on congestive heart failure mortality remains unknown, diuretics remain a vital component of symptomatic congestive heart failure management. Over time, sodium and water excretion are equalized before adequate fluid elimination occurs. This phenomenon is thought to occur in one out of three patients with congestive heart failure on diuretic therapy and is termed diuretic resistance. In congestive heart failure, both pharmacokinetic and pharmacodynamic alterations are thought to be responsible for diuretic resistance. Due to disease chronicity, symptomatic management is vital to improved quality of life and enhancing diuretic response is therefore pivotal.

This multiple case series was initially designed as a prospective, open-label, 12-week trial investigation evaluating memantine (Namenda) for the treatment of psychiatric and cognitive symptoms associated with PTSD. In a selected, small sample of individuals (n = 4) with combat PTSD, treatment with memantine produced consistent improvement on a delayed recall measure of memory, variable reduction of depressive symptoms, and variable reduction in hyperarousal symptoms. These data suggest potential positive treatment outcomes, both cognitively and psychiatrically, and provide rationale for future double-blind, placebo-controlled studies of memantine in PTSD.

BACKGROUND: Treatment options for chronic rhinosinusitis with recurrent polyposis (CRSwNP) after endoscopic sinus surgery (ESS) are limited, and include frequent use of systemic steroids and revision surgery. A bioabsorbable, steroid-eluting implant was studied for its ability to dilate sinuses obstructed by polyps and provide localized, controlled steroid delivery to reestablish sinus patency. This study assessed the initial feasibility, safety, and efficacy of steroid-eluting implants placed in the office setting in patients who were candidates for revision ESS. METHODS: Prospective, multicenter study enrolling 12 patients who had prior ESS but experienced recurrent polyposis refractory to medical therapy. Implants were placed bilaterally under topical anesthesia in-office. Follow-up through 6 months included endoscopic grading, patient-reported outcomes (22-item Sino-Nasal Outcomes Test [SNOT-22]) and need for revision ESS. RESULTS: Implants were successfully inserted in 21 of 24 (88%) ethmoid sinuses, resulting in 11 evaluable patients. No serious adverse events occurred. Within 1 month, mean bilateral polyp grade was reduced from 4.5 at baseline to 2.3 (p = 0.008) and sustained through 6 months (2.33; p = 0.008). Mean SNOT-22 score was significantly improved from 2.19 at baseline to 0.90 within 1 month (p = 0.001) and sustained to 6 months (1.03; p = 0.012). Sixty-four percent of patients were no longer revision ESS candidates at 6 months. CONCLUSION: The study provided initial clinical evidence of the feasibility, safety, and efficacy of in-office steroid-eluting implant placement in CRS patients with recurrent polyposis after ESS. Although further studies are needed, the results suggest this therapy may provide a safe and effective, office-based option for the treatment of obstructive polyposis.

UNLABELLED: Several plasma non-lipid biomarkers have been shown to predict major cardiovascular events (MCVEs) in population studies. Our objective was to investigate the relationship between lipid and non-lipid biomarkers levels achieved during statin therapy and the incidence of MCVEs in patients with stable coronary heart disease (CHD). We conducted a substudy of the TNT (Treating to New Targets) study, which was a randomized trial that compared the efficacy of high (80 mg) versus low (10 mg) dose atorvastatin for the secondary prevention of CHD. Fasting plasma levels of standard lipids and of 18 non-lipid biomarkers were obtained after an 8-week run-in period on atorvastatin 10 mg in 157 patients who experienced MCVEs during the 4.9 years of study follow-up and in 1349 controls. MCVE was defined as CHD death, nonfatal, non-procedure-related myocardial infarction, resuscitated cardiac arrest, and fatal or nonfatal stroke. After adjusting for age, sex and treatment arm, plasma levels of high-density lipoprotein (HDL) cholesterol, triglycerides, high-sensitivity C-reactive protein (hsCRP), insulin, neopterin, N-terminal pro-brain natriuretic peptide (BNP), lipoprotein(a) [Lp(a)], and the soluble receptor for advanced glycation end products (sRAGE) were predictive of recurrent MCVEs (P ≤ 0.02 for each doubling of plasma concentration). However, no significant association was observed between the risk of recurrent MCVEs and plasma levels of low-density lipoprotein cholesterol, adiponectin, cystatin C, lipoprotein-associated phospholipase A2, monocyte chemotactic protein-1, matrix metalloproteinase-9, myeloperoxidase, osteopontin, soluble CD40 ligand, soluble intercellular adhesion molecule-1, or soluble vascular cell adhesion molecule-1. After further adjustment for diabetes, hypertension, smoking, and BMI, the relationship between hsCRP, insulin and MCVE were no longer significant, while the relationship between Lp(a), neopterin, NT-proBNP and sRAGE and MCVE remained statistically significant. In conclusion, in patients with CHD treated with atorvastatin, plasma levels of Lp(a), neopterin, NT-proBNP, and sRAGE are associated with the risk of recurrent MCVEs. TRIAL REGISTRATION: ClinicalTrials.gov NCT00327691.