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Biomedical subjects

David A Schoenfeld

Publications and source records attributed to David A Schoenfeld.

At least 19 recordsLinked to original sources
PubMed2026

Distinct endogenous retroviruses are expressed in mutational subtypes of clear cell renal cell carcinoma and are linked to improved clinical outcomes.

Distinct mutations in chromatin regulators and aberrant expression of transposable elements (TEs), have been associated with clinical benefit to immunotherapy (IO) in specific clear cell renal cell carcinoma (ccRCC) clinical contexts. However, the relationship between mutations in chromatin regulators and TE expression, and their effect on clinical outcomes, are incompletely understood. Here, we identified TEs expressed in distinct mutational subtypes of ccRCC, with endogenous retroviruses (ERVs) comprising the majority of TEs observed. Of these, ERVs 544 and 2014 were upregulated in PBRM1 mutant samples. Patients with high expression of these ERVs and somatic PBRM1 mutations had improved progression-free survival with IO monotherapy, but not targeted therapy, and their upregulation associated with expression of innate immune pathways. Chromatin accessibility increased at ERV 544 and 2014 loci in PBRM1-deficient ccRCC cells, and ERV 544 and 2014 were upregulated upon in vitro PBRM1 knockout in ccRCC cell line clones. Broadly, our study supports a link between PBRM1 mutations, subsequent chromatin accessibility changes, and aberrant but immunoresponsive ERVs in ccRCC.

CP: cancer↗
PubMed2006

Survival analysis of longitudinal microarrays.

MOTIVATION: The development of methods for linking gene expressions to various clinical and phenotypic characteristics is an active area of genomic research. Scientists hope that such analysis may, for example, describe relationships between gene function and clinical events such as death or recovery. Methods are available for relating gene expression to measurements that are categorized or continuous, but there is less work in relating expressions to an observed event time such as time to death, response or relapse. When gene expressions are measured over time, there are methods for differentiating temporal patterns. However, methods have not yet been proposed for the survival analysis of longitudinally collected microarrays. RESULTS: We describe an approach for the survival analysis of longitudinal gene expression data. We construct a measure of association between the time to an event and gene expressions collected over time. Statistical significance is addressed using permutations and control of the false discovery rate. Our proposed method is illustrated on a dataset from a multi-center research study of inflammation and response to injury that aims to uncover the biological reasons why patients can have dramatically different outcomes after suffering a traumatic injury (www.gluegrant.org).

Algorithms↗
PubMed2006

Trial of celecoxib in amyotrophic lateral sclerosis.

OBJECTIVE: To determine whether chronic treatment with celecoxib, a cyclooxygenase-2 inhibitor that has been shown to be beneficial in preclinical testing, is safe and effective in amyotrophic lateral sclerosis (ALS). METHODS: A double-blind, placebo-controlled, clinical trial was conducted. Three hundred research subjects with ALS were randomized (2:1) to receive celecoxib (800 mg/day) or placebo for 12 months. The primary outcome measure was the rate of change in upper extremity motor function measured by the maximum voluntary isometric contraction strength. Secondary end points included safety, survival, change in cerebrospinal fluid prostaglandin E(2) levels, and changes in the rate of decline of leg and grip strength, vital capacity, ALS Functional Rating Scale-Revised, and motor unit number estimates. RESULTS: Celecoxib did not slow the decline in muscle strength, vital capacity, motor unit number estimates, ALS Functional Rating Scale-Revised, or affect survival. Celecoxib was well tolerated and was not associated with an increased frequency of adverse events. Prostaglandin E(2) levels in cerebrospinal fluid were not elevated at baseline and did not decline with treatment. INTERPRETATION: At the dosage studied, celecoxib did not have a beneficial effect on research subjects with ALS, and it was safe. A biological effect of celecoxib was not demonstrated in the cerebrospinal fluid. Further studies of celecoxib at a dosage of 800 mg/day in ALS are not warranted.

Adult↗
PubMed2006

Glucose metabolism in patients with schizophrenia treated with olanzapine or quetiapine: a frequently sampled intravenous glucose tolerance test and minimal model analysis.

OBJECTIVE: Clozapine and olanzapine treatment has been associated with insulin resistance in non-obese schizophrenia patients. Much less is known regarding other agents such as quetiapine. The objective of this study was to compare matched olanzapine- and quetiapine-treated schizophrenia patients and normal controls on measures of glucose metabolism. METHOD: A cross-sectional comparison of quetiapine-treated and olanzapine-treated non-obese (body mass index < 30.0 kg/m2) schizophrenia subjects (DSM-IV) with matched normal controls using a frequently sampled intravenous glucose tolerance test and nutritional assessment was conducted from April 2002 to October 2004. Data from 24 subjects were included in the analysis (7 quetiapine, 8 olanzapine, 9 normal controls). RESULTS: There was a significant difference among groups for fasting baseline plasma glucose concentrations (p = .02), with olanzapine greater than normal controls (p = .01). The insulin sensitivity index (SI) differed significantly among groups (p = .039); olanzapine subjects exhibited significant insulin resistance compared to normal controls (p = .01), but there was no significant difference for quetiapine versus olanzapine (p = .1) or quetiapine versus normal controls (p = .40). SI inversely correlated with quetiapine dose (p = .0001) and waist circumference (p = .03) in quetiapine-treated subjects. Insulin resistance calculated by the homeostasis model assessment of insulin resistance (HOMA-IR) also differed significantly among groups (p = .03). The olanzapine group had a higher HOMA-IR level than normal controls (p = .01). There was a significant difference in glucose effectiveness (SG) among the groups (p = .049). SG was lower in the olanzapine group than in the quetiapine group (p = .03) and in the olanzapine group compared to normal controls (p = .049). CONCLUSIONS: Our findings are consistent with our previous report that nonobese olanzapine-treated subjects showed insulin resistance, measured by both HOMA-IR and SI, and reduction in SG. Studies that include larger samples, unmedicated patients, and varying durations of antipsychotic exposure are necessary to confirm these results.

Adult↗
PubMed2005

Application of genome-wide expression analysis to human health and disease.

The application of genome-wide expression analysis to a large-scale, multicentered program in critically ill patients poses a number of theoretical and technical challenges. We describe here an analytical and organizational approach to a systematic evaluation of the variance associated with genome-wide expression analysis specifically tailored to study human disease. We analyzed sources of variance in genome-wide expression analyses performed with commercial oligonucleotide arrays. In addition, variance in gene expression in human blood leukocytes caused by repeated sampling in the same subject, among different healthy subjects, among different leukocyte subpopulations, and the effect of traumatic injury, were also explored. We report that analytical variance caused by sample processing was acceptably small. Blood leukocyte gene expression in the same individual over a 24-h period was remarkably constant. In contrast, genome-wide expression varied significantly among different subjects and leukocyte subpopulations. Expectedly, traumatic injury induced dramatic changes in apparent gene expression that were greater in magnitude than the analytical noise and interindividual variance. We demonstrate that the development of a nation-wide program for gene expression analysis with careful attention to analytical details can reduce the variance in the clinical setting to a level where patterns of gene expression are informative among different healthy human subjects, and can be studied with confidence in human disease.

Cluster Analysis↗
PubMed2005

A double-blind placebo-controlled trial of bupropion sustained-release for smoking cessation in schizophrenia.

The objective of this study was to examine the efficacy of bupropion for smoking cessation in patients with schizophrenia. Adults with schizophrenia who smoked more than 10 cigarettes per day and wished to try to quit smoking were recruited from community mental health centers, enrolled in a 12-week group cognitive behavioral therapy intervention, and randomly assigned to receive either bupropion sustained-release 300 mg/d or identical placebo. Fifty-three adults, 25 on bupropion and 28 on placebo, were randomized, completed at least 1 postbaseline assessment and were included in the analysis. The primary outcome measures were 7-day point prevalence abstinence in the week after the quit date (week 4) and at the end of the intervention (week 12). Subjects in the bupropion group were significantly more likely to be abstinent for the week after the quit date (36% [9/25] vs. 7% [2/28], P = 0.016) and at end of the intervention (16% [4/25] vs. 0%, P = 0.043). Subjects in the bupropion group also had a higher rate of 4-week continuous abstinence (weeks 8-12) (16% [4/25] vs. 0%, P = 0.043) and a longer duration of abstinence (4.2 [3.2] weeks vs. 1.8 [0.96] weeks, t = 2.30, P = 0.037). The effect of bupropion did not persist after discontinuation of treatment. Subjects in the bupropion group had no worsening of clinical symptoms and had a trend toward improvement in depressive and negative symptoms. We conclude that bupropion does not worsen clinical symptoms of schizophrenia and is modestly effective for smoking cessation in patients with schizophrenia. The relapse rate is high after treatment discontinuation.

Adult↗
PubMed2005

Prevalence and significance of anti-HLA and donor-specific antibodies long-term after renal transplantation.

Post-transplant circulating anti-human leukocyte antigens (HLA)-antibodies and C4d in allograft biopsies may be important in chronic rejection in renal transplant recipients (RTR). We determined the prevalence and significance of anti-HLA-antibodies and donor-specific antibodies (DSA). Sera were collected from 251 RTR >6 months post-transplant. Sera were tested using enzyme-linked immunosorbent assay (ELISA) screening for anti-HLA antibodies. Positive sera were retested with ELISA-specific panel for antibody specificity. A 11.2% of patients had anti-HLA antibodies and 4.4% had DSA. Anti-HLA antibodies were significantly associated with pretransplant sensitization, acute rejection and in multivariate analysis, higher serum creatinine (2.15 +/- 0.98 vs. 1.57 +/- 0.69 mg/dl in negative anti-HLA antibodies group). Allograft biopsies performed in a subset of patients with anti-HLA antibodies revealed that 66% had C4d in peritubular capillaries (0% in patients without antibodies). Anti-HLA antibodies were associated with a worse allograft function and in situ evidence of anti-donor humoral alloreactivity. Long-term RTR with an increase in creatinine could be screened for anti-HLA antibodies and C4d in biopsy.

Adolescent↗
PubMed2005

Independent effects of tobacco abstinence and bupropion on cognitive function in schizophrenia.

OBJECTIVE: The objective of this study was to examine the effects of tobacco abstinence and bupropion treatment on cognitive functioning in adult smokers with schizophrenia in the setting of a randomized, double-blind, placebo-controlled clinical trial of bupropion for smoking cessation. METHOD: Fifty-three adults with schizophrenia (DSM-IV) took part in a trial of bupropion for smoking cessation. Subjects were enrolled in the study from August 1999 to March 2003. Forty-five subjects remained in the trial at week 4; 41 subjects, 19 taking bupropion and 22 taking placebo, completed the baseline and week 4 cognitive assessments and were included in the analysis of adjusted effects of abstinence and bupropion treatment on cognitive function. RESULTS: Controlling for bupropion treatment and baseline performance, 7 days of tobacco abstinence was associated with slowed motor speed (finger tapping) but was not associated with worsening of performance on tests of attention (AX Continuous Performance Test [AX-CPT]), verbal learning and memory (California Verbal Learning Test [CVLT]), working memory (digit span), or executive function/inhibition (Stroop) and was not associated with worsening of any clinical measures. Controlling for abstinence status, bupropion was associated with reduction (improvement) in reaction time variability on the AX-CPT and with reduction in perseverative errors on the CVLT. CONCLUSION: We conclude that 1 week of tobacco abstinence is associated with slowed motor speed but is not associated with detectable worsening in performance on a range of neuropsychological tests or clinical symptoms in the subset of patients who were able to quit smoking. We also conclude that bupropion treatment may be associated with improvement in variability of attention.

Adult↗
PubMed2004

Pro/con clinical debate: It is acceptable to stop large multicentre randomized controlled trials at interim analysis for futility. Pro: Futility stopping can speed up the development of effective treatments.

A few recent, large, well-publicized trials in critical care medicine have been stopped for futility. In the critical care setting, stopping for futility means that independent review committees have elected to stop the trial early--based on predetermined rules--since the likelihood of finding a treatment effect is low. For bedside clinicians the idea of futility in a clinical trial can be confusing. In the present article, two experts in the conduct of clinical trials debate the role of futility-stopping rules.

Attitude of Health Personnel↗
PubMed2004

Effect of granulocyte colony-stimulating factor on functional and histopathologic outcome after traumatic brain injury in mice.

OBJECTIVE: Granulocyte colony-stimulating factor has been used to reduce the risk of sepsis in patients with traumatic brain injury. However, granulocyte colony-stimulating factor exerts potent pro- and anti-inflammatory effects that could influence secondary injury, and outcome, after traumatic brain injury. Our objective was to determine the effect of granulocyte colony-stimulating factor on histopathologic, motor, and cognitive outcome after experimental traumatic brain injury in mice. DESIGN: Experimental study. SETTING: Research laboratory at the Massachusetts General Hospital, Boston, MA. SUBJECTS: Forty-eight adult male C57Bl/6 mice. INTERVENTIONS: Mice (8 wks of age, n = 16/group) were administered granulocyte colony-stimulating factor or saline subcutaneously twice per day for 7 days after controlled cortical impact or sham injury (n = 16). Absolute neutrophil counts, motor function, Morris water maze performance, and lesion volume were determined after controlled cortical impact or sham injury. MEASUREMENTS AND MAIN RESULTS: At the time of controlled cortical impact, body weight, brain and body temperature, and systemic absolute neutrophil counts did not differ between groups. Compared with control, systemic absolute neutrophil count was increased more than ten-fold in granulocyte colony-stimulating factor-treated mice on posttrauma days 2 and 7 (p < .05, repeated-measures analysis of variance) but did not differ between groups by day 14. There were no differences between groups in tests of motor function or histopathologic outcome. However, compared with control, mice given granulocyte colony-stimulating factor had improved Morris water maze performance after controlled cortical impact (p < .05, repeated-measures analysis of variance) but not sham injury. CONCLUSIONS: The data suggest a small beneficial effect of granulocyte colony-stimulating factor on functional outcome after traumatic brain injury in adult mice but do not show differences in histopathology or motor outcome between treated and control groups.

Analysis of Variance↗
PubMed2003

Modelling the relationship between continuous covariates and clinical events using isotonic regression.

In a medical study we are often interested in graphically displaying the relationship between continuous variables and clinical events indicating disease progression. Often, it is reasonable to make the minimal assumption that the risk of progression is an arbitrary monotone function of the continuous variable. Sometimes the continuous variable is a disease marker which is recorded longitudinally, and so the goal is to provide a graphical display of the relationship between the hazard for progression and the most recent measurement of the longitudinal marker. For example, we know that for a patient with HIV infection, declining CD4 count is associated with an increased risk of opportunistic infection. The goal of this paper is to extend isotonic regression techniques to failure time data with a continuous covariate, to obtain a non-parametric estimate for the hazard of disease progression as a monotonic function of the continuous variable. We propose two methods for modelling the relationship of the hazard and covariate: the first assumes that the hazard is constant over time, and the second allows the hazard to be an arbitrary function of time. These methods will be applied to graphically display the risk for an AIDS patient of an opportunistic infection as a function of CD4 count.

AIDS-Related Opportunistic Infections↗
PubMed2003

Differential effects of androgens and estrogens on bone turnover in normal men.

The physiologic role of androgens and estrogens in the maintenance of normal bone turnover in men is a fundamental issue in bone biology. To address this question, we randomized 70 men between the ages of 20 and 44 yr to receive one of three treatment regimens. Group 1 (n = 25) received a GnRH analog (goserelin acetate 3.6 mg by sc injection every 4 wk) alone for 12 wk to suppress endogenous gonadal steroids to prepubertal levels. Group 2 (n = 22) received goserelin plus transdermal testosterone (Androderm 5 mg topically daily) to normalize circulating testosterone and estradiol levels. Group 3 (n = 23) received goserelin plus testosterone plus an aromatase inhibitor (anastrozole 1 mg orally daily) to induce selective estrogen deficiency. The selective effects of androgens and estrogens on skeletal homeostasis were then assessed by measuring changes in biochemical markers of bone turnover and analyzing the between-group differences. Bone resorption markers increased in both the hypogonadal group (group 1) and in the group with selective estrogen deficiency (group 3). Urinary deoxypyridinoline excretion increased more in group 1 than in group 3 (P = 0.023), suggesting a significant effect of androgens on bone resorption, whereas serum N-telopeptide levels increased more in group 3 than in group 2 (P = 0.037), suggesting a significant effect of estrogen on bone resorption. Bone formation markers initially declined in all groups and then increased in groups 1 and 3. The between-group comparisons were consistent for all formation markers. Bone formation markers increased more in group 1 than in group 2 (P = 0.001, 0.037, 0.005 for osteocalcin, carboxy-terminal propeptide of type I procollagen, and amino-terminal propeptide of type I procollagen, respectively). Bone formation markers also increased more in group 1 than in group 3 but these differences were not statistically significant (P = 0.065 0.073, 0.099 for osteocalcin, carboxy-terminal propeptide of type I procollagen, and amino-terminal propeptide of type I procollagen, respectively). Taken together, these data suggest that both androgens and estrogens play independent and fundamental roles in regulating bone resorption in men. These data also suggest that androgens may play an important role in the regulation of bone formation in men.

Administration, Cutaneous↗
PubMed2002

Statistical evaluation of ventilator-free days as an efficacy measure in clinical trials of treatments for acute respiratory distress syndrome.

OBJECTIVE: Trials of potential new therapies in acute lung injury are difficult and expensive to conduct. This article is designed to determine the utility, behavior, and statistical properties of a new primary end point for such trials, ventilator-free days, defined as days alive and free from mechanical ventilation. Describing the nuances of this outcome measure is particularly important because using it, while ignoring mortality, could result in misleading conclusions. DESIGN: To develop a model for the duration of ventilation and mortality and fit the model by using data from a recently completed clinical trial. To determine the appropriate test statistic for the new measure and derive a formula for power. To determine a formula for the probability that the test statistic will reject the null hypothesis and mortality will simultaneously show improvement. To plot power curves for the test statistic and determine sample sizes for reasonable alternative hypotheses. SETTING: Intensive care units. PATIENTS: Patients with acute respiratory distress syndrome or acute lung injury as defined by the American-European Consensus Conference. MAIN RESULTS: The proposed model fit the clinical data. Ventilator-free days were improved by lower tidal volume ventilation, but the improvement was mostly caused by the improved mortality rate, so trials that expected similar effects would only have modest increase in power if they used ventilator-free days as their primary end point rather than 28-day mortality. Similar results were obtained using the model in two groups segregated by low or high Acute Physiology and Chronic Health Evaluation score. On the other hand, if patients are divided into two groups on the basis of the lung injury score, both the duration of ventilation and mortality are lower in the low lung injury score group. A trial of a treatment that had a similar clinical effect would have a large increase in power, allowing for a reduction in the required sample size. CONCLUSIONS: Use of ventilator-free days as a trial end point allows smaller sample sizes if it is assumed that the treatment being tested simultaneously reduces the duration of ventilation and improves mortality. It is unlikely that a treatment that led to higher mortality could lead to a statistically significant improvement in ventilator-free days. This would be especially true if the treatment were also required to produce a nominal improvement in mortality.

APACHE↗
PubMed2002

Incidence, outcome, and long-term consequences of herpes simplex virus type 1 reactivation presenting as a facial rash in intubated adult burn patients treated with acyclovir.

BACKGROUND: Increased mortality, extensive visceral involvement, and necrotizing tracheobronchitis associated with herpes viruses have been reported after burns. It is unclear whether herpes presenting as a facial rash results in outcome changes after burns. METHODS: A retrospective study characterizing the incidence, presentation, and outcome of 14 patients with facial herpes rashes out of 95 severely burned intubated adults was performed. RESULTS: Facial rashes attributed to herpetic infections were found in at least 15% of patients. The problem was recognized during the second week after burn. There was no difference in mortality or length of stay noted between patients with or without the infection. CONCLUSION: The course of this infection was relatively benign in this group of acyclovir-treated patients. Even so, the lesions clearly contributed to patient discomfort and often produced fevers requiring costly investigations. Early recognition could help prevent diffuse spread of the lesions, decreasing patient discomfort and improving patient care.

Acyclovir↗
PubMed2002

Analysis of failure time data with dependent interval censoring.

This article develops a method for the analysis of screening data for which the chance of being screened is dependent on the event of interest (informative censoring). Because not all subjects make all screening visits, the data on the failure of interest is interval censored. We propose a model that will properly adjust for the dependence to obtain an unbiased estimate of the nonparametric failure time function, and we provide an extension for applying the method for estimation of the regression parameters from a (discrete time) proportional hazards regression model. The method is applied on a data set from an observational study of cytomegalovirus shedding in a population of HIV-infected subjects who participated in a trial conducted by the AIDS Clinical Trials Group.

AIDS-Related Opportunistic Infections↗
PubMed2002

Abnormal bone mineral accrual in adolescent girls with anorexia nervosa.

Anorexia nervosa (AN) is increasingly common in adolescent girls and occurs at a time of peak bone mass formation. Osteopenia is common in adolescent girls with AN, and in a cross-sectional study, we have reported low bone formation markers in such girls. To determine the impact of chronic undernutrition on bone mineral accrual in contrast to healthy controls, we prospectively measured bone mineral density (BMD) and body composition by dual energy x-ray absorptiometry, bone metabolism markers, and nutritional and hormonal status at baseline, 6 months, and 12 months in 19 adolescent girls with AN (mean +/- SEM, 15.4 +/- 0.4 yr) and 19 controls of comparable chronological and skeletal age. Overall, nutritional status in subjects with AN improved (mean percentage increase in body mass index from baseline, 9.2 +/- 1.9% and 15.2 +/- 2.6% at 6 and 12 months, respectively), with 11 subjects having recovered weight at 12 months. However, lumbar BMD at 12 months (AN, 0.88 +/- 0.02 g/cm(2), vs. control, 0.98 +/- 0.03 g/cm(2); P = 0.008) remained significantly reduced in AN compared with controls, even in recovered subjects. This was due to significant increases in lumbar BMD in controls vs. no change in AN subjects over the year (0.003 +/- 0.001 g/cm(2).month vs. 0.000 +/- 0.001 g/cm(2).month, respectively; P = 0.04). The most significant determinant of change in lumbar BMD at 12 months was change in lean body mass in both AN (r = 0.62; P = 0.008) and control (r = 0.80; P = 0.0006) groups. There were significant increases in surrogate markers of bone turnover in subjects with AN compared with controls as assessed by osteocalcin (AN, 0.9 +/- 0.4 micro g/liter.month, vs. control, -1.1 +/- 0.4 micro g/liter.month; P = 0.0007), bone-specific alkaline phosphatase (AN, 0.6 +/- 0.5 U/liter.month, vs. control, -1.5 +/- 0.4 U/liter.month; P = 0.002), deoxypyridinoline [AN, 0.1 +/- 0.1 nmol/mmol creatinine (cr).month, vs. control, -0.4 +/- 0.1 nmol/mmol cr.month; P = 0.005], and N-telopeptide (AN, 4 +/- 4 nmol BCE/mmol cr/month, vs. control, -9 +/- 4 nmol BCE/mmol cr/month; P = 0.01). Changes in IGF-I levels over the year were highly correlated with changes in bone turnover over the same period in AN (osteocalcin, r = 0.77; P = 0.001; deoxypyridinoline, r = 0.66; P = 0.01). A rise in N-telopeptide over the year was correlated with an increase in all bone mineral measures, including lumbar bone mineral content (r = 0.58; P = 0.03) and BMD (r = 0.53; P = 0.05) and total bone mineral content (r = 0.69; P = 0.006) and BMD (r = 0.69; P = 0.006) in the AN group. Therefore, despite recovery over 1 yr, poor bone mineral accrual persists in adolescent girls with AN in contrast to rapid bone accrual in healthy girls. Normalization of bone turnover markers occurs in association with nutritional recovery and an increase in the nutritionally dependent bone trophic factor IGF-I. A rise in bone turnover markers may be an early indicator of increase in BMD in recovering girls with AN.

Adipose Tissue↗