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Biomedical subjects

L Chan

Publications and source records attributed to L Chan.

At least 73 records · Page 4Linked to original sources
PubMed2000

Hammerhead ribozyme as a therapeutic agent for hyperlipidemia: production of truncated apolipoprotein B and hypolipidemic effects in a dyslipidemia murine model.

In humans, overproduction of apolipoprotein B (apoB) is positively associated with premature coronary artery diseases. To reduce the levels of apoB mRNA, we used adenovirus-mediated vector to target hammerhead ribozyme at GUA(6679) downward arrow of apoB mRNA (designated AvRB15) in the liver of a dyslipidemic mouse model that is deficient in apoB mRNA editing enzyme and overexpresses human apoB100. In this study, we delivered approximately 4 x 10(11) virus particles of AvRB15 (active ribozyme) or AvRB15-mutant (inactive ribozyme) to the animals. Using Southern blot analysis, we readily detected RB15 DNA in the mouse liver as long as day 35 after injection. This result was correlated with the RNA expression of RB15 by RNase protection assay. Using reverse ligation-mediated polymerase chain reaction, the 3' cleavage product of apoB mRNA was detected, and the exact cleavage site was confirmed by sequencing. Importantly, the levels of human and mouse apoB mRNA decreased approximately 80% after AvRB15 transduction. There was a marked decrease in plasma cholesterol, triglyceride, and human apoB of 42, 51, and 62%, respectively, when compared with the inactive ribozyme-treated group. Moreover, ribozyme cleavage of apoB mRNA generated a truncated protein of the expected size (apoB48.1), which was associated with lipoprotein particles in the very low density, low density, and high density lipoprotein fractions. Taken together, these results indicate that apoB mRNA-specific hammerhead ribozyme can be used as a potential therapeutic agent to modulate apoB gene expression and to treat hyperlipidemia.

Animals↗
PubMed2000

Synthesis and antiviral activities of N-9-oxypurine 1,3-dioxolane and 1,3-oxathiolane nucleosides.

Two series of 1,3-dioxolanes and 1,3-oxathiolane nucleosides containing N-9-oxypurine were synthesized as potential antiviral agents. These compounds were prepared by reacting the sugar moieties with iodo- or bromotrimethylsilane, followed by treatment with a mixture of sodium hydride and the desired N-hydroxy purine base. The preparation of these N-hydroxybases was also described. No significant antiviral activity was observed against HIV, HBV, HSV-1, HSV-2, or HCMV.

Anti-HIV Agents↗
PubMed2000

Treatment of acute myocardial infarction and 30-day mortality among women and men.

BACKGROUND: Previous studies have suggested that women with acute myocardial infarction receive less aggressive therapy than men. We used data from the Cooperative Cardiovascular Project to determine whether women and men who were ideal candidates for therapy after acute myocardial infarction were treated differently. METHODS: Information was abstracted from the charts of 138,956 Medicare beneficiaries (49 percent of them women) who had an acute myocardial infarction in 1994 or 1995. Multivariate analysis was used to assess differences between women and men in the medications administered, the procedures used, the assignment of do-not-resuscitate status, and 30-day mortality. RESULTS: Among ideal candidates for therapy, women in all age groups were less likely to undergo diagnostic catheterization than men. The difference was especially pronounced among older women; for a woman 85 years of age or older, the adjusted relative risk was 0.75 (95 percent confidence interval, 0.68 to 0.83). Women were somewhat less likely than men to receive thrombolytic therapy within 60 minutes (adjusted relative risk, 0.93; 95 percent confidence interval, 0.90 to 0.96) or to receive aspirin within 24 hours after arrival at the hospital (adjusted relative risk, 0.96; 95 percent confidence interval, 0.95 to 0.97), but they were equally likely to receive beta-blockers (adjusted relative risk, 0.99; 95 percent confidence interval, 0.95 to 1.03) and somewhat more likely to receive angiotensin-converting-enzyme inhibitors (adjusted relative risk, 1.05; 95 percent confidence interval, 1.02 to 1.08). Women were more likely than men to have a do-not-resuscitate order in their records (adjusted relative risk, 1.26; 95 percent confidence interval, 1.22 to 1.29). After adjustment, women and men had similar 30-day mortality rates (hazard ratio, 1.02; 95 percent confidence interval, 0.99 to 1.04). CONCLUSIONS: As compared with men, women receive somewhat less aggressive treatment during the early management of acute myocardial infarction. However, many of these differences are small, and there is no apparent effect on early mortality.

Adrenergic beta-Antagonists↗
PubMed2000

Apolipoprotein B, a paradigm for proteins regulated by intracellular degradation, does not undergo intracellular degradation in CaCo2 cells.

Studies in different liver-derived cells in culture indicate that apolipoprotein (apo) B-100 production is regulated largely by intracellular degradation and the ubiquitin-proteasome pathway is a major mechanism for the degradation. The proteasomal degradation of apoB-100 was postulated to be an intrinsic property of the protein that occurs even in the presence of optimal amounts of lipids supplied to the cell. We examined apoB-100 and apoB-48 biogenesis in CaCo2, a human colon carcinoma cell line. To our surprise, apoB-100 and apoB-48 were quantitatively secreted by CaCo2 cells; essentially none of the newly synthesized apoB was degraded before secretion in a 2-h period whether the cells were cultured on filter or on plastic. Furthermore, although ubiquitin immunoreactivity was readily detected in the intracellular apoB isolated from HepG2 cells, little or no ubiquitin was detectable in the intracellular apoB from CaCo2 cells. The amounts of free ubiquitin and total and non-apoB ubiquitinated proteins were comparable in HepG2 and CaCo2 cells, indicating that CaCo2 cells have the necessary machinery for tagging ubiquitin chains onto cellular proteins for proteasomal degradation. Incubation in lipoprotein-deficient serum did not induce apoB degradation, but the addition of a microsomal triglyceride transfer protein inhibitor led to apoB degradation in CaCo2 cells. Finally, similar proportions of apoB polypeptide in isolated microsomes from CaCo2 and HepG2 cells were accessible to exogenously added trypsin, indicating that the mere exposure of apoB nascent chains to the cytosolic compartment is insufficient to cause the proteasomal degradation. Therefore, the intracellular degradation of apoB is not an intrinsic property of the protein, and the phenomenon is neither universal nor inevitable. The unconditional use of apoB as a paradigm for intracellular protein degradation is not warranted.

Apolipoprotein B-100↗
PubMed2000

P-Selectin or intercellular adhesion molecule (ICAM)-1 deficiency substantially protects against atherosclerosis in apolipoprotein E-deficient mice.

The expression of leukocyte and endothelial cell adhesion molecules (CAMs) is essential for the emigration of leukocytes during an inflammatory response. The importance of the inflammatory response in the development of atherosclerosis is indicated by the increased expression of adhesion molecules, proinflammatory cytokines, and growth factors in lesions and lesion-prone areas and by protection in mice deficient in various aspects of the inflammatory response. We have quantitated the effect of deficiency for intercellular adhesion molecule (ICAM)-1, P-selectin, or E-selectin on atherosclerotic lesion formation at 20 wk of age in apolipoprotein (apo) E(-/-) (deficient) mice fed a normal chow diet. All mice were apo E(-/-) and CAM(+/+) or CAM(-/-) littermates, and no differences were found in body weight or cholesterol levels among the various genotypes during the study. ICAM-1(-/-) mice had significantly less lesion area than their ICAM-1(+/+) littermates: 4.08 +/- 0.70 mm(2) for -/- males vs. 5.87 +/- 0.66 mm(2) for +/+ males, and 3.95 +/- 0. 65 mm(2) for -/- females vs. 5.59 +/- 1.131 mm(2) for +/+ females, combined P < 0.0001. An even greater reduction in lesion area was observed in P-selectin(-/-) mice: 3.06 +/- 1.04 mm(2) for -/- males vs. 5.09 +/- 1.22 mm(2) for +/+ males, and 2.85 +/- 1.26 mm(2) for -/- females compared with 5.60 +/- 1.19 mm(2) for +/+ females, combined P < 0.001. The reduction in lesion area for the E-selectin null mice, although less than that seen for ICAM-1 or P-selectin, was still significant (4.54 +/- 2.14 mm(2) for -/- males vs. 5.92 +/- 0.63 mm(2) for +/+ males, and 4.38 +/- 0.85 mm(2) for -/- females compared with 5.94 +/- 1.44 mm(2) for +/+ females, combined P < 0.01). These results, coupled with the closely controlled genetics of this study, indicate that reductions in the expression of P-selectin, ICAM-1, or E-selectin provide direct protection from atherosclerotic lesion formation in this model.

Animals↗
PubMed2000

Two-dimensional electrophoresis map of the human hepatocellular carcinoma cell line, HCC-M, and identification of the separated proteins by mass spectrometry.

Currently, one of the most popular applications of proteomics is in the area of cancer research. In Africa, Southeast Asia, and China, hepatocellular carcinoma is one of the most common cancers, occurring as one of the top five cancers in frequency. This project was initiated with the purpose of separating and identifying the proteins of a human hepatocellular carcinoma cell line, HCC-M. After two-dimensional gel electrophoresis separation, silver staining, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) analyses, tryptic peptide masses were searched for matches in the SWISS-PROT and NCBI nonredundant databases. Approximately 400 spots were analyzed using this approach. Among the proteins identified were housekeeping proteins such as alcohol dehydrogenase, alpha-enolase, asparagine synthetase, isocitrate dehydrogenase, and glucose-6-phosphate 1-dehydrogenase. In addition, we also identified proteins with expression patterns that have been postulated to be related to the process of carcinogenesis. These include 14-3-3 protein, annexin, prohibitin, and thioredoxin peroxidase. This study of the HCC-M proteome, coupled with similar proteome analyses of normal liver tissues, tumors, and other hepatocellular carcinoma cell lines, represents the first step towards the establishment of protein databases, which are valuable resources in studies on the differential protein expressions of human hepatocellular carcinoma.

Carcinoma, Hepatocellular↗
PubMed2000

Manual wheelchair pushrim biomechanics and axle position.

OBJECTIVE: The biomechanics of wheelchair propulsion have been linked to upper extremity injury. Specifically, prior studies have correlated increased median nerve dysfunction with increasing propulsion frequency and a higher rate of rise of the resultant, or total, pushrim force. Despite this link, there is little research on the effect of wheelchair setup on propulsion biomechanics. The objective of this study was to determine the effect of rear axle position relative to the shoulder on pushrim biomechanics. DESIGN: Case series. SETTING: Biomechanics laboratory. PARTICIPANTS: Forty individuals with paraplegia who use manual wheelchairs for mobility. INTERVENTION: Subjects propelled their own wheelchairs on a dynamometer at two different steady-state speeds and going from a dead stop to maximum speed. Bilateral biomechanical data were obtained using a force- and moment-sensing pushrim and a motion analysis system. MAIN OUTCOME MEASURES: Position of the axle relative to the shoulder at rest both horizontal (XPOS) and vertical (YPOS), and pushrim biomechanical variables including frequency of propulsion, peak and rate of rise of the resultant force, planar moment, and push angle. Partial correlation coefficients between relative axle position and propulsion biomechanics variables were calculated. RESULTS: After controlling for subject characteristics, XPOS was significantly correlated with the frequency of propulsion (p < .01) and the rate of rise of the resultant force (p < .05). In addition, both XPOS and YPOS were significantly correlated with the push angle at multiple speeds (p < .05). CONCLUSION: Specific biomechanical parameters known to correlate with median nerve injuries were found to be related to axle position relative to the shoulder. Providing wheelchair users with adjustable axle position and then fitting the user to the wheelchair can improve propulsion biomechanics and likely reduce the risk of injury.

Adult↗
PubMed2000

Medicare's payment system: its effect on discharges to skilled nursing facilities from rehabilitation hospitals.

OBJECTIVE: To determine if Medicare's payment system for rehabilitation hospitals encourages discharges to skilled nursing facilities (SNFs). Medicare payments to hospitals are based on limits derived from a hospital's average allowable patient charge during a base year. Thereafter, payments are capped, but hospitals receive additional incentive payments if succeeding costs are reduced. It was a hypothesis of this study that discharges to SNFs would increase after the base year. In this way, rehabilitation hospitals would limit high-cost patients when under reimbursement limitation. METHODS: Medicare claims data for 162,239 discharges from 69 rehabilitation hospitals between 1987 and 1994 were analyzed. After controlling for patient and provider characteristics, we compared the odds of being discharged to a SNF before, during, and after the base year. RESULTS: Before and during the base year, 4.7% and 6.6% of patients were discharged to a SNF. After the base year, 9% of patients were sent to a SNF. After controlling for temporal and seasonal trends, as well as for patient and provider characteristics, those discharged after the base year were significantly more likely to be sent to a SNF than those discharged during the base year. These odds increased with increasing length of stay in the rehabilitation hospital. For those with a length of stay of 29 days (75th percentile) the odds increased by 11% (odds ratio, 1.11; 95% confidence interval, 1.04-1.18). CONCLUSIONS: The incentives of Medicare's reimbursement system may encourage an increase in the percentage of patients discharged to SNFs after the base year. These findings have significant implications regarding the structure of Medicare's prospective payment system currently planned for this class of hospital.

Female↗
PubMed2000

The db/db mouse, a model for diabetic dyslipidemia: molecular characterization and effects of Western diet feeding.

Diabetic dyslipidemia is a major factor contributing to the accelerated atherosclerosis in type 2 diabetes mellitus. Although several mouse models are available, the plasma lipoproteins in response to diet have not been fully characterized in these animals. In this study, we have characterized the plasma lipoproteins and related apolipoproteins, as well as the vascular lipases, in diabetes (db/db) mice and their nondiabetic controls (+/?) in the C57BL/KsJ strain. Within 6 weeks of age, db/db mice developed significant obesity, fasting hyperglycemia, and hyperinsulinemia. By FPLC analysis, db/db mice showed a prominent peak in the low-density lipoprotein (LDL) range that was absent in +/? mice, although high-density lipoprotein (HDL) was the predominant species in both groups of animals. Postheparin lipoprotein lipase (LPL) activity in db/db mice was 28% of the level in +/? mice. Upon feeding a human-like 0.15% (wt/wt) cholesterol and 21% (wt/wt) fat "Western" diet, db/db mice developed elevated plasma cholesterol, accompanied by an exaggerated apolipoprotein E (apoE) response compared with +/? mice. FPLC analysis showed that the marked hypercholesterolemic response in db/db mice was the result of a massive increase in the LDL region, which overshadowed a moderate increase in HDL. We next isolated lipoproteins by ultracentrifugation and characterized them by nondenaturing gradient gel electrophoresis. With regular chow, db/db mice had almost exclusively small dense LDL with a peak size at 21.4 nm, as compared with 26.6 nm in nondiabetic controls. On the Western diet, the small dense LDLs persisted but larger particles also appeared in db/db mice, whereas the size distribution in +/? mice was unchanged by the diet. Our results suggest that db/db mice fed a Western diet have a plasma lipoprotein phenotype that shows some similarities to that in patients with type 2 diabetes mellitus, and that db/db mice are a useful model to study the pathogenesis and treatment of diabetic dyslipidemia.

Age Factors↗
PubMed2000

Absence of perilipin results in leanness and reverses obesity in Lepr(db/db) mice.

Obesity is a disorder of energy balance. Hormone-sensitive lipase (HSL) mediates the hydrolysis of triacylglycerol, the major form of stored energy in the body. Perilipin (encoded by the gene Plin), an adipocyte protein, has been postulated to modulate HSL activity. We show here that targeted disruption of Plin results in healthy mice that have constitutively activated fat-cell HSL. Plin -/- mice consume more food than control mice, but have normal body weight. They are much leaner and more muscular than controls, have 62% smaller white adipocytes, show elevated basal lipolysis that is resistant to beta-adrenergic agonist stimulation, and are cold-sensitive except when fed. They are also resistant to diet-induced obesity. Breeding the Plin -/- alleles into Leprdb/db mice reverses the obesity by ncreasing the metabolic rate of the mice. Our results demonstrate a role for perilipin in reining in basal HSL activity and regulating lipolysis and energy balance; thus, agents that inactivate perilipin may prove useful as anti-obesity medications.

Adipose Tissue↗
PubMed2000

Relationship between fetal monitoring and resuscitative needs: fetal distress versus routine cesarean deliveries.

BACKGROUND: There is debate as to whether pediatricians should be present at all cesarean deliveries. Little published data exist regarding the differences in resuscitative needs of infants delivered by cesarean section for "fetal distress" versus those without this diagnosis. OBJECTIVE: To describe the differences in resuscitative and immediate postnatal intervention needs for neonates with fetal distress delivered by cesarean section and those without fetal distress delivered in the same manner. Also, to devise an evaluation tool to assess and compare levels of neonatal resuscitation between infants and groups of infants. METHODS: The delivery records of 1411 term infants delivered by cesarean section after uncomplicated pregnancies at Los Angeles County/University of Southern California Medical Center from March 3, 1995 through March 8, 1997 were examined retrospectively. Apgar scores and resuscitative needs were assigned to a newly devised, weighted scoring system. Resuscitation subscores and total resuscitation scores were compared using non-parametric methods. RESULTS: The fetal distress group (n = 80) had a significantly greater resuscitative needs mean score (p < 0.001) and subscores (p < 0.001 to p = 0.004) than did the non-fetal distress group (n = 419). Of the non-fetal distress group, 48.7% still received some active form of intervention. CONCLUSION: In our study group, infants with fetal distress had significantly greater intervention needs than infants without fetal distress.

Cesarean Section↗
PubMed2000

Compound heterozygosity of Leu252Val and Leu252Arg causing lipoprotein lipase deficiency in a chinese patient with hypertriglyceridemia.

BACKGROUND: We investigated lipoprotein lipase (LPL) gene mutations in a Chinese male with severe hypertriglyceridemia and recurrent pancreatitis. METHODS: We screened for LPL sequence mutation in the LPL gene in this patient, his relatives and 160 unrelated hypertriglyceridaemic subjects. We determined the postheparin plasma LPL activity of subjects carrying a LPL mutation and studied the in vitro expression of mutant LPL in COS-1 cells. RESULTS: The proband was found to be a compound heterozygote for a novel Leu252Val and a reported Leu252Arg mutation in the LPL gene. He had low plasma levels of postheparin LPL activity and mass. The two mutations segregated independently in his family. In vitro expression analysis showed that Leu252Arg abolished both the catalytic function and secretion of LPL, while Leu252Val abolished the catalytic function but only reduced secretion by about half. We have also detected heterozygous Leu252Val and Leu252Arg mutations each in one hypertriglyceridaemic individual. CONCLUSION: These results indicated that the leucine 252 is critical for the catalytic activity and secretion of LPL. Why the substitution by valine instead of arginine resulted only in a partial suppression of LPL secretion, remains to be investigated. Leu252Val and Leu252Arg are the likely cause of hypertriglyceridemia in these subjects because of their deleterious effects on LPL activity or secretion. Leu252Val/Leu252Arg is the first compound heterozygous mutation known to occur in the same codon of the LPL gene. So far they are found only in Chinese.

Adolescent↗
PubMed2000

The comparative accuracy of radiolucent foreign body detection using ultrasonography.

The purpose of this prospective study was to determine the accuracy of ultrasonography in detecting radiolucent foreign bodies and to compare the performance of three newly trained emergency physicians with two experienced ultrasound technologists and one radiologist. One hundred-four chicken thighs were penetrated with a needle-driver, half of them embedded with a 1.5 cm toothpick. An 8.0 MHZ linear array ultrasound probe was used to detect the presence or absence of the foreign body. The overall accuracy (95% confidence interval [CI]) was 82% (79, 85); sensitivity 79% (74, 83), specificity 86% (82, 90), positive predicative value (PPV) 85% (81, 89), and negative predicative value (NPV) 80% (76, 84). The accuracy (95% CI) of the radiologist was 83% (75, 90); of the ultrasound technologists was 85% (80, 90); and of the emergency physicians was 0% (76, 85). The difference in accuracy among the three types of personnel was not statistically significant. Ultrasonography is an accurate modality in detecting radiolucent foreign bodies. Emergency physicians can be trained to provide a degree of accuracy comparable with more experienced ultrasonographers.

Allied Health Personnel↗
PubMed2000

The association between meconium and the production and reabsorption of lung liquid and lactate loss by in vitro lungs from fetal guinea pigs.

OBJECTIVE: We sought to use an in vitro approach to determine relationships between meconium and fetal lung liquid production and to relate meconium to possible problems in lung liquid removal at birth. STUDY DESIGN: Near-term fetal guinea pigs were divided according to the level of spontaneously occurring meconium (no meconium, light meconium, or heavy meconium). Their lungs were maintained in vitro in Krebs-Henseleit saline solution for 3 hours. Lung liquid production or reabsorption was measured by a dye-dilution method, and loss of lactate to the lung liquid and outer Krebs-Henseleit solution was monitored. Reabsorptions were investigated by activating powerful responses with dinitrophenol during the middle hour. RESULTS: During the first hour, lungs from meconium-free fetuses produced liquid at 1.25 +/- 0.12 mL/kg(-1) body weight. h(-1); rates from light or heavy meconium groups were not significantly different (n = 18). Similarly, total lactate loss was not significantly different between the meconium-free and light-meconium groups but was twice as high in heavy-meconium preparations (73.68 +/- 10.60 micromol/L. g(-1) dry lung tissue. h(-1); P <.025, analysis of variance). The meconium-free and heavy-meconium groups continued to produce fluid, with no significant change throughout the 3 hours of incubation; lactate losses fell slightly. Therefore there were no problems with fluid production with meconium present, but the high-lactate losses with heavy meconium suggested long-term intrauterine hypoxia. Dinitrophenol produced powerful reabsorptions in lungs from meconium-free fetuses (-0.85 +/- 0.35 mL. kg(-1) body weight. h(-1); P <.005, analysis of variance; P <.0005, regression analysis) but failed to do so in heavy-meconium fetuses (n = 36). Lactate losses rose 2-fold in both groups (P <.005 to P < 0.0005, analysis of variance and regression analysis), despite already elevated losses with heavy meconium (n = 12). Therefore, in heavy-meconium fetuses, dinitrophenol affected metabolic pathways but did not activate fluid reabsorption, suggesting damage to reabsorptive mechanisms. CONCLUSION: Unless major airways are blocked, meconium is not associated with reduced fetal lung liquid production, which can cause poor lung development, but there may well be poor fluid removal after birth because of compromised reabsorptive mechanisms, which are unlikely to be helped by possible hormonal intervention.

Absorption↗
PubMed2000

Perceived risk and help-seeking behavior for breast cancer. A Chinese-American perspective.

Delay in the diagnosis and treatment of breast cancer diminishes a woman's chance of survival. How do women decide whether and when to seek an evaluation of breast symptoms that may signal breast cancer? Prior studies of African-American, white, and Latino women have described a number of critical factors associated with making the judgment to delay, but at this writing, there have been no studies factors influencing Chinese-American women. By means of focus group methods in English, Mandarin, and Cantonese, a sample of 45, predominantly first-generation Chinese-American women explained their understanding of breast cancer risk and their likelihood of delaying versus seeking evaluation of self-discovered breast symptoms. There was much congruence with the ideas of other American women despite the differing cultural heritage. Unique to these Chinese Americans was a sense of invulnerability to breast cancer, a linking of cancer to tragic luck, and the predominant likelihood of delay. To preserve modesty and to conserve wealth and time, many study participants favored using Chinese medicine and delaying Western therapies. This study suggests ways by which health care providers must approach guidelines for breast cancer early detection in this population.

Adult↗
PubMed2000

Effect of prehospital advanced life support on outcomes of major trauma patients.

OBJECTIVE: Determine whether prehospital advanced life support (ALS) improves the survival of major trauma patients and whether it is associated with longer on-scene times. METHODS: A 36-month retrospective study of all major trauma patients who received either prehospital bag-valve-mask (BVM) or endotracheal intubation (ETI) and were transported by paramedics to our Level I trauma center. Logistic regression analysis determined the association of prehospital ALS with patient survival. RESULTS: Of 9,451 major trauma patients, 496 (5.3%) had either BVM or ETI. Eighty-one percent received BVM, with a mean Injury Severity Score of 29 and a mortality rate of 67%; 93 patients (19%) underwent successful ETI, with a mean Injury Severity Score of 35 and a mortality rate of 93%. Adjusted survival for patients who had BVM was 5.3 times more likely than for patients who had ETI (95% confidence interval, 2.3-14.2, p = 0.00). Survival among patients who received intravenous fluids was 3.9 times more likely than those who did not (p = not significant). Average on-scene times for patients who had ETI or intravenous fluids were not significantly longer than those who had BVM or no intravenous fluids. CONCLUSION: ALS procedures can be performed by paramedics on major trauma patients without prolonging on-scene time, but they do not seem to improve survival.

Adolescent↗