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Biomedical subjects

J Klar

Publications and source records attributed to J Klar.

At least 19 recordsLinked to original sources
PubMed2006

A founder mutation for ichthyosis prematurity syndrome restricted to 76 kb by haplotype association.

Autosomal recessive congenital ichthyosis (ARCI) is a group of keratinisation disorders that includes the ichthyosis prematurity syndrome (IPS). IPS is rare and almost exclusively present in a restricted region in the middle of Norway and Sweden, which indicates a founder effect for the disorder. We recently reported linkage of IPS to chromosome 9q34, and we present here the subsequent fine-mapping of this region with known and novel microsatellite markers as well as single nucleotide polymorphisms (SNPs). Allelic association, evaluated with Fisher's exact test and P (excess), was used to refine the IPS haplotype to approximately 1.6 Mb. On the basis of the average length of the haplotype in IPS patients, we calculated the age of a founder mutation to approximately 1,900 years. The IPS haplotype contains a core region of 76 kb consisting of four marker alleles shared by 97.7% of the chromosomes associated with IPS. This region spans four known genes, all of which are expressed in mature epidermal cells. We present the results from the analysis of these four genes and their corresponding transcripts in normal and patient-derived samples.

Alleles↗
PubMed2003

Hospital care of osteoporosis-related vertebral fractures.

Resource implications of hospitalization for osteoporosis-related vertebral fracture are sparsely documented. This study utilized data abstracted from a national sample of hospitalized patients to identify characteristics of patients who are hospitalized with vertebral fracture and their patterns of resource utilization. These were compared with patterns observed for hip fracture hospitalizations. Data from the Nationwide Inpatient Sample (NIS) for 1997 were used to identify men and women age 45 years and above who had a primary diagnosis of vertebral fracture. After patients whose fractures might have been due to metastatic cancer or severe trauma were excluded, 68,901 individuals hospitalized for vertebral fracture were identified. Seventy-seven percent of these were women, most were white, 75 years and older, and had multiple comorbid diagnoses. Total charges averaged 8000-10,000 US dollars per hospitalization and were higher in men. Mean length of stay was just under 6 days and more than 50% of discharged patients required some form of continuing care. Hospitalizations for vertebral fracture occurred at only one-fourth the rate of those for hip fracture, and created only half the hospital charges per admission. Vertebral fracture accounted for over 400,000 total hospital days and generated charges in excess of 500 million US dollars. This resource impact is considerably higher than has been described in prior studies.

Age Distribution↗
PubMed1999

[Liver metastasis?].

Explore the source record for details and available documents.

Diagnosis, Differential↗
PubMed1999

Truncating ribosomal protein S19 mutations and variable clinical expression in Diamond-Blackfan anemia.

Diamond-Blackfan anemia (DBA) is a rare constitutional erythroblastopenia characterized by a specific defect in erythroid differentiation. Recently, mutations in the gene encoding ribosomal protein (RP) S19 were found in a subset of patients with the disease. To characterize further RPS19 mutations and to investigate genotype-phenotype relationships, we screened this gene for mutations in patients with DBA by direct sequencing and Southern-blot analysis. Four novel mutations were identified. A G120A nonsense mutation resulting in a stop at codon 33, a C302T nonsense mutation introducing a premature stop at codon 84, and a 327delG which results in a frame shift at codon 103. A fourth and more complex mutation (TT157-158AA, 160insCT) resulting in a Leu45Gln and a frame shift from codon 47 was found in three affected family members with variable phenotypes. The different clinical expression for identical mutations suggest the presence of other modulating factors for the disease. The mutations presented here further support the role of RPS19 in erythropoietic differentiation and proliferation.

Adult↗
PubMed1999

The gene encoding ribosomal protein S19 is mutated in Diamond-Blackfan anaemia.

Diamond-Blackfan anaemia (DBA) is a constitutional erythroblastopenia characterized by absent or decreased erythroid precursors. The disease, previously mapped to human chromosome 19q13, is frequently associated with a variety of malformations. To identify the gene involved in DBA, we cloned the chromosome 19q13 breakpoint in a patient with a reciprocal X;19 chromosome translocation. The breakpoint occurred in the gene encoding ribosomal protein S19. Furthermore, we identified mutations in RPS19 in 10 of 40 unrelated DBA patients, including nonsense, frameshift, splice site and missense mutations, as well as two intragenic deletions. These mutations are associated with clinical features that suggest a function for RPS19 in erythropoiesis and embryogenesis.

Amino Acid Sequence↗
PubMed1998

Multicenter outcome study of cancer patients admitted to the intensive care unit: a probability of mortality model.

PURPOSE: To develop prospectively and validate a model for probability of hospital survival at admission to the intensive care unit (ICU) of patients with malignancy. PATIENTS AND METHODS: This was an inception cohort study in the setting of four ICUs of academic medical centers in the United States. Defined continuous and categorical variables were collected on consecutive patients with cancer admitted to the ICU. A preliminary model was developed from 1,483 patients and then validated on an additional 230 patients. Multiple logistic regression modeling was used to develop the models and subsequently evaluated by goodness-of-fit and receiver operating characteristic (ROC) analysis. The main outcome measure was hospital survival after ICU admission. RESULTS: The observed hospital mortality rate was 42%. Continuous variables used in the ICU admission model are PaO2/FiO2 ratio, platelet count, respiratory rate, systolic blood pressure, and days of hospitalization pre-ICU. Categorical entries include presence of intracranial mass effect, allogeneic bone marrow transplantation, recurrent or progressive cancer, albumin less than 2.5 g/dL, bilirubin > or = 2 mg/dL, Glasgow Coma Score less than 6, prothrombin time greater than 15 seconds, blood urea nitrogen (BUN) greater than 50 mg/dL, intubation, performance status before hospitalization, and cardiopulmonary resuscitation (CPR). The P values for the fit of the preliminary and validation models are .939 and .314, respectively, and the areas under the ROC curves are .812 and .802. CONCLUSION: We report a disease-specific multivariable logistic regression model to estimate the probability of hospital mortality in a cohort of critically ill cancer patients admitted to the ICU. The model consists of 16 unambiguous and readily available variables. This model should move the discussion regarding appropriate use of ICU resources forward. Additional validation in a community hospital setting is warranted.

Academic Medical Centers↗
PubMed1996

The Logistic Organ Dysfunction system. A new way to assess organ dysfunction in the intensive care unit. ICU Scoring Group.

OBJECTIVE: To develop an objective method for assessing organ dysfunction among intensive care unit (ICU) patients on the first day of the ICU stay. DESIGN AND SETTING: Physiological variables defined dysfunction in 6 organ systems. Logistic regression techniques were used to determine severity levels and relative weights for the Logistic Organ Dysfunction (LOD) score and for conversion of the LOD score to a probability of mortality. PATIENTS: A total of 13 152 consecutive admission to 137 adult medical/surgical ICUs in 12 countries from the European/North American Study of Severity Systems. OUTCOME MEASURES: Patient vital status at hospital discharge. RESULTS: The LOD System identified from 1 to 3 levels of organ dysfunction for 6 organ systems: neurologic, cardiovascular, renal, pulmonary, hematologic, and hepatic. From 1 to 5 LOD points were assigned to the levels of severity, and the resulting LOD scores ranged from 0 to 22 points. Model calibration was very good in the developmental and validation samples (P=.21 and P=.50, respectively), as was model discrimination (area under the receiver operating characteristic curves of 0.843 and 0.850, respectively). CONCLUSION: The LOD System provides an objective tool for assessing severity levels for organ dysfunction in the ICU, a critical component in the conduct of clinical trials. Neurologic, cardiovascular, and renal dysfunction were the most severe organ dysfunctions, followed by pulmonary and hematologic dysfunction, with hepatic dysfunction the least severe. The LOD System takes into account both the relative severity among organ systems and the degree of severity within an organ system.

Adult↗
PubMed1996

Factors affecting the performance of the models in the Mortality Probability Model II system and strategies of customization: a simulation study.

OBJECTIVES: To examine the impact of hospital mortality and intensive care unit (ICU) size on the performance of the Mortality Probability Model II system for use in quality assessment, and to examine the ability of model customization to produce accurate estimates of hospital mortality to characterize patients by severity of illness for clinical trials. DESIGN: Prospective evaluation of model performance, using retrospective data. SETTING: Data for the simulation were assembled from six adult medical and surgical ICUs in Massachusetts and New York. PATIENTS: Consecutive admissions (n = 4,224) to the Massachusetts and New York ICUs were studied. The mortality rate in the database was 18.7%. INTERVENTIONS: A computer simulation of several different hospital mortality rates and ICU sample sizes, using a multicenter database of consecutive ICU admissions, was utilized. We simulated 20 different mortality rates by randomly changing the outcomes at hospital discharge from "survived" to "deceased" and from "deceased" to "survived". Four sample size simulations used 75%, 50%, 25%, and 10% of the database. Ten replications of each mortality rate and samples size were constructed, and model calibration and discrimination were assessed for each replication. Model coefficients were customized, using logistic regression. MEASUREMENTS AND MAIN RESULTS: Vital status at hospital discharge was the outcome measure among the ICU patient population. Model performance was assessed using the Hosmer-Lemeshow C statistic for calibration, and the area under the receiver operating characteristic curve for discrimination. Goodness-of-fit tests and receiver operating characteristic curve areas demonstrated that the models were sensitive to differences in hospital mortality, indicating that they are useful quality assurance tools. Goodness-of-fit tests were more sensitive than the receiver operating characteristic curve areas. The further the hospital mortality rate diverged from the original rate, the worse the performance of the model. Sample size had an impact on these results. The smaller the sample size, the less likely the model was to perform poorly. Model coefficients were successfully customized to demonstrate that improved model performance can be achieved when necessary for clinical trial stratification. CONCLUSION: Mortality Probability Model II models can be used to assess quality of care in ICUs, but the size of the sample should be considered when assessing calibration and discrimination.

Adult↗
PubMed1995

Customized probability models for early severe sepsis in adult intensive care patients. Intensive Care Unit Scoring Group.

OBJECTIVE: To develop customized versions of the Simplified Acute Physiology Score II (SAPS II) and the 24-hour Mortality Probability Model II (MPM II) to estimate the probability of mortality for intensive care unit patients with early severe sepsis. DESIGN AND SETTING: Logistic regression models developed for patients with severe sepsis in a database of adult medical and surgical intensive care units in 12 countries. PATIENTS: Of 11,458 patients in the intensive care unit for at least 24 hours, 1130 had severe sepsis based on criteria of the American College of Chest Physicians and the Society of Critical Care Medicine (systemic inflammatory response syndrome in response to infection, plus hypotension, hypoperfusion, or multiple organ dysfunction). RESULTS: In patients with severe sepsis, mortality was higher (48.0% vs 19.6% among other patients) and 28-day survival was lower. The customized SAPS II was well calibrated (P = .92 for the goodness-of-fit test) and discriminated well (area under the receiver operating characteristic [ROC] curve, 0.78). Performance in the validation sample was equally good (P = .85 for the goodness-of-fit test; area under the ROC curve, 0.79). The customized MPM II was well calibrated (P = .92 for the goodness-of-fit test) and discriminated well (area under the ROC curve, 0.79). Performance in the validation sample was equally good (P = .52 for the goodness-of-fit test; area under the ROC curve, 0.75). The models are independent of each other; either can be used alone to estimate the probability of mortality of patients with severe sepsis. CONCLUSIONS: Customization provides a simple technique to apply existing models to a subgroup of patients. Accurately assessing the probability of hospital mortality is a useful adjunct for clinical trials.

Adult↗
PubMed1995

Outcome prediction for individual intensive care patients: useful, misused, or abused?

Probabilities of hospital mortality provide meaningful information in many contexts, such as in discussions of patient prognosis by intensive care physicians, in patient stratification for analysis of clinical trial data by researchers, and in hospital reimbursement analysis by insurers. Use of probabilities as binary predictors based on a cut point can be misleading for making treatment decisions for individual patients, however, even when model performance is good overall. Alternative models for estimating severity of illness in intensive care unit (ICU) patients, while demonstrating good agreement for describing patients in the aggregate, are shown to differ considerably for individual patients. This suggests that identifying patients unlikely to benefit from ICU care by using models must be approached with considerable caution.

Bias↗
PubMed1994

A retrospective-cohort study of occupational exposure to hexavalent chromium.

A retrospective cohort study was conducted to examine the risk of mortality, cancer, and other adverse health outcomes, at the United States' largest chromate chemicals manufacturing facility in Castle Hayne, North Carolina. This facility, built in 1971, was designed to reduce the high levels of chromium exposure found at most older facilities. Exposure assessment was based on analysis of more than 5,000 personal breathing zone samples collected over a 15-year period. A questionnaire was used to collect relevant occupational, medical, smoking, and other information from current and former employees. Analysis of the cohort's mortality experience found no substantial departures from that expected based on external comparisons, although evidence of a healthy worker effect was observed. Internal cohort analyses were limited by relatively small numbers; however, a subgroup of employees who transferred from older facilities was found to have higher risks of mortality (odds ratio = 1.27 for each 3 years of previous exposure; 90% confidence interval (CI) = 1.07-1.51) and cancer (odds ratio = 1.22 for each 3 years of previous exposure; 90% CI = 1.03-1.45). While this subgroup represented only 11% of the individuals in this study, they accounted for 46% (6/13) of all observed cancers (excluding skin cancers) and 60% (3/5) of lung cancers. There was no increased risk of mortality or cancer among employees who worked only at the newer facility. As an etiologic research study, the results are limited by the relatively small number of subjects and short follow-up; nevertheless, the findings can be used to design and implement a prospective surveillance system for monitoring the health of chromate production workers.

Carcinogens, Environmental↗
PubMed1994

Mortality probability models for patients in the intensive care unit for 48 or 72 hours: a prospective, multicenter study.

OBJECTIVE: To develop models in the Mortality Probability Model (MPM II) system to estimate the probability of hospital mortality at 48 and 72 hrs in the intensive care unit (ICU), and to test whether the 24-hr Mortality Probability Model (MPM24), developed for use at 24 hrs in the ICU, can be used on a daily basis beyond 24 hrs. DESIGN: A prospective, multicenter study to develop and validate models, using a cohort of consecutive admissions. SETTING: Six adult medical and surgical ICUs in Massachusetts and New York adjusted to reflect 137 ICUs in 12 countries. PATIENTS: Consecutive admissions (n = 6,290) to the Massachusetts/New York ICUs were studied. Of these patients, 3,023 and 2,233 patients remained in the ICU and had complete data at 48 and 72 hrs, respectively. Patients < 18 yrs of age, burn patients, coronary care patients, and cardiac surgical patients were excluded. OUTCOME MEASURE: Vital status at the time of hospital discharge. RESULTS: The models consist of five variables measured at the time of ICU admission and eight variables ascertained at 24-hr intervals. The 24-hr model demonstrated poor calibration and discrimination at 48 and 72 hrs. The newly developed 48- and 72-hr models--MPM48 and MPM72--contain the same 13 variables and coefficients as the MPM24. The models differ only in their constant terms, which increase in a manner that reflects the increasing probability of mortality with increasing length of stay in the ICU. These constant terms were adjusted by a factor determined from the relationship between the data from the six Massachusetts and New York ICUs and a more extensive data set, from which the ICU admission Mortality Probability Model (MPM0) and MPM24 were developed. This latter data set was assembled from ICUs in 12 countries. The MPM48 and MPM72 calibrated and discriminated well, based on goodness-of-fit tests and area under the receiver operating characteristic curve. CONCLUSIONS: Models developed for use among ICU patients at one time period are not transferable without modification to other time periods. The MPM48 and MPM72 calibrated well to their respective time periods, and they are intended for use at specific points in time. The increasing constant terms and associated increase in the probability of hospital mortality exemplify a common clinical adage that if a patient's clinical profile stays the same, he or she is actually getting worse.

Adult↗
PubMed1993

Mortality Probability Models (MPM II) based on an international cohort of intensive care unit patients.

OBJECTIVE: To revise and update models in the Mortality Probability Model (MPM II) system to estimate the probability of hospital mortality among 19,124 intensive care unit (ICU) patients that can be used for quality assessment within and among ICUs. DESIGN AND SETTING: Models developed and validated on consecutive admissions to adult medical and surgical ICUs in 12 countries. PATIENTS: A total of 12,610 patients for model development, 6514 patients for model validation. Patients younger than 18 years and burn, coronary care, and cardiac surgery patients were excluded. OUTCOME MEASURE: Vital status at hospital discharge. RESULTS: The admission model, MPM0, contains 15 readily obtainable variables. In developmental and validation samples it calibrated well (goodness-of-fit tests: P = .623 and P = .327, respectively, where a high P value represents good fit between observed and expected values) and discriminated well (area under the receiver operating characteristic curve = 0.837 and 0.824, respectively). The 24-hour model, MPM24 (developed on 10,357 patients still in the ICU at 24 hours), contains five of the admission variables and eight additional variables easily ascertained at 24 hours. It also calibrated well (P = .764 and P = .231 in the developmental and validation samples, respectively) and discriminated well (area under the receiver operating characteristic curve = 0.844 and 0.836 in the developmental and validation samples, respectively). CONCLUSIONS: Among severity systems for intensive care patients, the MPM0 is the only model available for use at ICU admission. Both MPM0 and MPM24 are useful research tools and provide important clinical information when used alone or together.

Adult↗
PubMed1989

Improvement of myocardial function by trifluoperazine, a calmodulin antagonist, after acute coronary artery occlusion and coronary revascularization.

Activation of an intracellular calcium-calmodulin complex may play an important role in myocardial injury induced by ischemia and reperfusion. Trifluoperazine, a calmodulin antagonist, was used before ischemia to enhance myocardial preservation by preventing intracellular calcium accumulation. The experimental model used an isolated in situ pig heart (19 control animals and 15 trifluoperazine-treated animals) subjected to occlusion of the left anterior descending coronary artery for 60 minutes followed by 60 minutes of hypothermic potassium crystalloid cardioplegic arrest and 60 minutes of reperfusion. Myocardial segmental function measured by ultrasonic crystals showed that active systolic segment shortening was abolished in the distribution of the left anterior descending artery after 60 minutes of occlusion irrespective of the treatment, whereas that not in the distribution of the left anterior descending artery increased by about 15% in both groups of animals. Restoration of systolic segment shortening in the distribution of the left anterior descending artery 60 minutes after reperfusion was 12% and 42% of baseline levels in untreated and trifluoperazine-treated animals, respectively (p less than 0.01). This improvement in segmental function by trifluoperazine was reflected in significantly (p less than 0.05) better global myocardial contractility and compliance and in significantly (p less than 0.01) greater total coronary blood flow and myocardial oxygen consumption. Trifluoperazine also increased myocardial creatine phosphate content in the distribution of the left anterior descending artery (p less than 0.01) during reperfusion, and creatine kinase release was reduced (p less than 0.05). Our results suggest that trifluoperazine improved regional myocardial function after acute occlusion of the left anterior descending artery and reperfusion and that global cardiac performance was thereby improved. The beneficial effects of trifluoperazine may be exerted by prevention of myocardial injury associated with the calcium-calmodulin complex in ischemic and reperfused myocardium.

Adenosine Triphosphate↗
PubMed1988

Sample size requirements for studies estimating odds ratios or relative risks.

This paper presents formulae for determining the number of subjects necessary, in either a case-control or a cohort study, to estimate the odds ratio or relative risk, respectively, to within a selected percentage (epsilon) of the true population value with some specified probability. This approach differs somewhat from previous comparable work that estimated the log odds ratio within a stated fixed distance rather than as a percentage of the actual odds ratio. Comparable development for relative risk has not previously appeared in the literature. These formulae provide guidelines for determination of study size that does not depend on hypothesis testing considerations.

Epidemiologic Methods↗
PubMed1988

Prospective study of clinical bleeding in intensive care unit patients.

We investigated prospectively clinical bleeding in 1,328 consecutive patients admitted to a medical/surgical ICU over 1 yr. One hundred thirty-eight (10.4%) patients bled after ICU admission, and an additional 388 (29.2%) bled coincident with admission. The upper GI tract was the site of bleeding in 34.8% of patients whose bleeds commenced in the ICU, and accounted for 22% of total sites. Patients with clinical bleeding after ICU admission had a significantly (p less than .001) higher likelihood of death than those who did not bleed, and those with multiple bleeding sites had a higher mortality (54.9%) than those with single sites (31%) (p less than .006). Multiple logistic regression analyses revealed that risk ratios (RR) for bleeding after ICU admission were mechanical ventilation (RR = 1.82), nutritional failure (RR = 3.45), acute renal failure (RR = 3.36), antiulcer medication (RR = 3.36), and anticoagulants (RR = 4.19). No antibiotics could be specifically incriminated. This study defines the scope, characteristics, and importance of bleeding in ICU patients and establishes risk factors.

Aged↗
PubMed1986

Enhanced bleeding with cefoxitin or moxalactam. Statistical analysis within a defined population of 1493 patients.

Most cases of beta-lactam-associated coagulopathy occur in patients with other risk factors. This study analyzed temporally related clinical bleeding events in 1493 patients who received one antibiotic for at least three days. Univariate and multivariate analyses controlled for condition variables (nutritional status, renal, hepatic, or hematologic dysfunction, intensive care unit stay) and treatment variables (use of antiplatelet agents, anticoagulants, vitamin K, antitumor chemotherapy or antiulcer therapy, steroids) that could have been associated with bleeding independently. Rates of bleeding ranged from 0% (chloramphenicol sodium succinate, vancomycin hydrochloride, erythromycin lactobionate) to 8.2% (cefoxitin) to 22.2% (moxalactam disodium). Multiple logistic regression analyses revealed that only moxalactam (odds ratio, 9.9) and cefoxitin (odds ratio, 2.1) exhibited significantly higher likelihoods of bleeding than other agents. This study statistically confirms increased risk of bleeding with moxalactam, heretofore reported only anecdotally. Cefoxitin may carry risks greater than previously believed.

Anti-Bacterial Agents↗