High Hospital Occupancy Is Associated with Increased Risk for Patients Boarding in the Emergency Department.

Am J Med. 2012 Feb 3;

Authors: Zhou JC, Pan KH, Zhou DY, Zheng SW, Zhu JQ, Xu QP, Wang CL

Abstract
BACKGROUND: Boarding admitted patients in the emergency department due to high hospital occupancy is a worldwide problem. However, whether or not emergency department-boarded patients managed by emergency department providers subjects them to increased serious complications needs further clarification. METHODS: A multivariate logistic regression analysis was used to examine the relationship of patient's age, sex, arrival hours, diagnostic category, triage category, daily emergency department visits, and daily hospital occupancy to the occurrence of serious complications within 24 hours for 20,276 emergency admissions in a 4-year period. RESULTS: A vast majority of study days (86.5%) saw very high occupancy ?90%. Serious complications incidence was 13.62 per 1000 patient days when hospital occupancy was ?90%, and it increased significantly to 17.10 and 22.52 per 1000 patient days for occupancy at 90%-95% and ?95%, respectively. In the multivariate analysis, significant risk factors for serious complications included daily occupancy ?95% (adjusted odds ratio [OR] 1.73; 95% confidence interval [CI], 1.26-2.39), triage category (adjusted OR 0.20; 95% CI, 0.17-0.24), and specific diagnoses (injury and poisoning [adjusted OR 1.62; 95% CI, 1.22-2.84], respiratory [adjusted OR 2.48; 95% CI, 1.37-4.49], and circulatory [adjusted OR 3.24; 95% CI, 1.80-5.80]). CONCLUSION: High hospital occupancy was associated with an increased incidence of serious complications within 24 hours for patients admitted but still boarded in the emergency department and managed by emergency department providers.

PMID: 22306273 [PubMed - as supplied by publisher]

Anticoagulation-associated adverse drug events.

Am J Med. 2011 Dec;124(12):1136-42

Authors: Piazza G, Nguyen TN, Cios D, Labreche M, Hohlfelder B, Fanikos J, Fiumara K, Goldhaber SZ

Abstract
PURPOSE: Anticoagulant drugs are among the most common medications that cause adverse drug events (ADEs) in hospitalized patients. We performed a 5-year retrospective study at Brigham and Women's Hospital to determine clinical characteristics, types, root causes, and outcomes of anticoagulant-associated ADEs.
METHODS: We reviewed all inpatient anticoagulant-associated ADEs, including adverse drug reactions (ADRs) and medication errors, reported at Brigham and Women's Hospital through the Safety Reporting System from May 2004 to May 2009. We also collected data about the cost associated with hospitalizations in which ADRs occurred.
RESULTS: Of 463 anticoagulant-associated ADEs, 226 were medication errors (48.8%), 141 were ADRs (30.5%), and 96 (20.7%) involved both a medication error and ADR. Seventy percent of anticoagulant-associated ADEs were potentially preventable. Transcription errors (48%) were the most frequent root cause of anticoagulant-associated medication errors, while medication errors (40%) were a common root cause of anticoagulant-associated ADRs. Death within 30 days of anticoagulant-associated ADEs occurred in 11% of patients. After an anticoagulant-associated ADR, most hospitalization expenditures were attributable to nursing costs (mean $33,189 per ADR), followed by pharmacy costs (mean $7451 per ADR).
CONCLUSION: Most anticoagulant-associated ADEs among inpatients result from medication errors and are, therefore, potentially preventable. We observed an elevated 30-day mortality rate among patients who suffered an anticoagulant-associated ADE and high hospitalization costs following ADRs. Further quality improvement efforts to reduce anticoagulant-associated medication errors are warranted to improve patient safety and decrease health care expenditures.

PMID: 22114827 [PubMed - indexed for MEDLINE]

Impact of resident workload and handoff training on patient outcomes.

Am J Med. 2012 Jan;125(1):104-10

Authors: Mueller SK, Call SA, McDonald FS, Halvorsen AJ, Schnipper JL, Hicks LS

PMID: 22195534 [PubMed - in process]

Safety of iodinated intravenous contrast medium administration in sickle cell disease.

Am J Med. 2012 Jan;125(1):100.e11-6

Authors: Campbell KL, Hud LM, Adams S, Andrel J, Ballas SK, Feldman AM, Axelrod D

Abstract
BACKGROUND: Increased sickling of erythrocytes following intravenous iodinated contrast has been described in patients with sickle cell disease. In vitro, the effect is correlated with the tonicity, viscosity, acidity, and ionic nature of contrast media. Less erythrocyte sickling is observed in vitro with second-generation low- and iso-osmolar contrast agents. Clinical impact of these newer intravenous contrast agents has not been investigated.
PURPOSE: To review adverse outcomes following contrast administration in a cohort of patients with sickle cell disease.
METHODS: Inpatients with sickle cell disease who received iodinated intravenous were identified. Medical records were reviewed for evidence of worsening crisis and occurrence of adverse events within 48 hours of contrast administration. Data points were further analyzed with the goal of identifying predictors of adverse outcome.
RESULTS: There were 132 imaging studies that met inclusion criteria in 79 patients, mostly with homozygous hemoglobin S. The low-osmolar contrast Optiray (Coviden Imaging Inc., Hazelwood, Mo) was used in 45%. Administration of fluids, Mucomyst (Bristol-Myers Squibb, New York, NY), oxygen, or blood transfusion preceded 58% of studies. Minor adverse events followed 16% of studies, with new or worsening pain being most common (12%). Contrast-induced nephropathy occurred in 1.5%, resolving in all cases. Prehydration was associated with a decreased incidence of adverse events (P=.02).
CONCLUSION: Adverse events related to intravenous contrast occur in sickle cell disease patients at a rate similar to the general population, without an increase in contrast-induced nephropathy. Subjective reports of new or worsening pain crisis do not translate to objective findings. Beneficial diagnostic imaging can be performed without increased risk of serious complication in this population.

PMID: 22195536 [PubMed - in process]

Drug-induced Hypertension: An Unappreciated Cause of Secondary Hypertension.

Am J Med. 2012 Jan;125(1):14-22

Authors: Grossman E, Messerli FH

Abstract
A myriad variety of therapeutic agents or chemical substances can induce either a transient or persistent increase in blood pressure, or interfere with the blood pressure-lowering effects of antihypertensive drugs. Some agents cause either sodium retention or extracellular volume expansion, or activate directly or indirectly the sympathetic nervous system. Other substances act directly on arteriolar smooth muscle or do not have a defined mechanism of action. Some medications that usually lower blood pressure may paradoxically increase blood pressure, or an increase in pressure may be encountered after their discontinuation. In general, drug-induced pressure increases are small and transient: however, severe hypertension involving encephalopathy, stroke, and irreversible renal failure have been reported. The deleterious effect of therapeutic agents is more pronounced in patients with preexisting hypertension, in those with renal failure, and in the elderly. Careful evaluation of a patient's drug regimen may identify chemically induced hypertension and obviate unnecessary evaluation and facilitate antihypertensive therapy. Once chemical-induced hypertension has been identified, discontinuation of the causative agent is recommended, although hypertension can often be managed by specific therapy and dose adjustment if continued use of the offending agent is mandatory. The present review summarizes the therapeutic agents or chemical substances that elevate blood pressure and their mechanisms of action.

PMID: 22195528 [PubMed - in process]

Renal Replacement Therapies for Prevention of Radiocontrast-induced Nephropathy: A Systematic Review.

Am J Med. 2012 Jan;125(1):66-78.e3

Authors: Cruz DN, Goh CY, Marenzi G, Corradi V, Ronco C, Perazella MA

Abstract
BACKGROUND: Radiocontrast-induced nephropathy (RCIN) is an important cause of acute kidney injury, increasing in-hospital and long-term mortality. It is controversial whether prophylactic renal replacement therapy (RRT) may reduce a patient's risk of RCIN when compared with standard medical therapy (SMT).
METHODS: We searched through PubMed and bibliographies of retrieved articles. Published studies of RRT for RCIN prevention in patients receiving radiocontrast were included. The primary endpoint was RCIN incidence, defined as an increase in serum creatinine ?0.5 mg/dL. Results were combined on the risk ratio (RR) scale. Random-effects models were used. Sensitivity analyses were defined a priori to evaluate the effects of RRT modality, study design, and sample size.
RESULTS: Nine randomized controlled and 2 nonrandomized trials were included (n = 1010 patients); 8 studies used hemodialysis (HD) and 3 used hemofiltration or hemodiafiltration. Nine studies had data for primary endpoint; RCIN incidence was 23.3% in the RRT group and 21.2% in SMT. RRT did not decrease RCIN incidence compared with SMT (risk ratio [RR] 1.02; 95% confidence interval [CI], 0.54-1.93); however, intertrial heterogeneity was high. In sensitivity analyses, limiting to only HD studies significantly reduced heterogeneity. HD appeared to increase RCIN risk (RR 1.61; 95% CI, 1.13-2.28) and had no effect on need for permanent RRT or progression to end-stage renal disease (RR 1.47; 95% CI, 0.56-3.89).
CONCLUSION: In this updated meta-analysis, periprocedural RRT did not decrease the incidence of RCIN compared with SMT. HD appears to actually increase RCIN risk.

PMID: 22195531 [PubMed - in process]

Skilled nursing facility referral and hospital readmission rates after heart failure or myocardial infarction.

Am J Med. 2012 Jan;125(1):100.e1-9

Authors: Chen J, Ross JS, Carlson MD, Lin Z, Normand SL, Bernheim SM, Drye EE, Ling SM, Han LF, Rapp MT, Krumholz HM

Abstract
BACKGROUND: Substantial hospital-level variation in the risk of readmission after hospitalization for heart failure (HF) or acute myocardial infarction (AMI) has been reported. Prior studies have documented considerable state-level variation in rates of discharge to skilled nursing facilities (SNFs), but evaluation of hospital-level variation in SNF rates and its relationship to hospital-level readmission rates is limited.
METHODS: Hospital-level 30-day all-cause risk-standardized readmission rates (RSRRs) were calculated using claims data for fee-for-service Medicare patients hospitalized with a principal diagnosis of HF or AMI from 2006-2008. Medicare claims were used to calculate rates of discharge to SNF following HF-specific or AMI-specific admissions in hospitals with ?25 HF or AMI patients, respectively. Weighted regression was used to quantify the relationship between RSRRs and SNF rates for each condition.
RESULTS: Mean RSRR following HF admission among 4101 hospitals was 24.7%, and mean RSRR after AMI admission among 2453 hospitals was 19.9%. Hospital-level SNF rates ranged from 0% to 83.8% for HF and from 0% to 77.8% for AMI. No significant relationship between RSRR after HF and SNF rate was found in adjusted regression models (P=.15). RSRR after AMI increased by 0.03 percentage point for each 1 absolute percentage point increase in SNF rate in adjusted regression models (P=.001). Overall, HF and AMI SNF rates explained <1% and 4% of the variation for their respective RSRRs.
CONCLUSION: SNF rates after HF or AMI hospitalization vary considerably across hospitals, but explain little of the variation in 30-day all-cause readmission rates for these conditions.

PMID: 22195535 [PubMed - in process]

Intracerebral Hemorrhage with Thrombolytic Therapy for Acute Pulmonary Embolism.

Am J Med. 2011 Nov 23;

Authors: Stein PD, Matta F, Steinberger DS, Keyes DC

Abstract
BACKGROUND: Intracranial hemorrhage is one of the dreaded complications of thrombolytic therapy for acute pulmonary embolism. We identified patients with pulmonary embolism who may be at relatively high risk of intracerebral hemorrhage from those selected for thrombolytic therapy by their physicians and presumably thought to be of reasonable risk. METHODS: The number of patients discharged from short-stay hospitals in the United States from 1998 to 2008 with pulmonary embolism who received thrombolytic therapy and the proportion with intracerebral hemorrhage were determined from the Nationwide Inpatient Sample, Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality. RESULTS: From 1998 to 2008, 2,237,600 patients were discharged with a diagnosis of pulmonary embolism. Among patients who received thrombolytic therapy for pulmonary embolism, the prevalence of intracerebral hemorrhage was 430 of 49,500 (0.9%). The prevalence increased linearly with age more than 10 years. Intracerebral hemorrhage was less frequent in those with a primary diagnosis of pulmonary embolism (250/39,300 [0.6%]) than in those with a secondary diagnosis (180/10,300 [1.7%], P<.0001). The prevalence of intracerebral hemorrhage was lower in patients aged 65 years or less with no kidney disease (90/16,900 [0.5%]) than in patients aged more than 65 years or with kidney disease (290/20,900 [1.4%], P<.0001). The prevalence remained lower in those with a primary diagnosis (90/23,000 [0.4%] than in those with a secondary diagnosis (50/5700 [0.9%], P<.0001). CONCLUSION: The cause of intracerebral hemorrhage in patients with pulmonary embolism who receive thrombolytic therapy seems to be multifactorial and related to comorbidity and age.

PMID: 22115025 [PubMed - as supplied by publisher]

Venous thromboembolism prophylaxis for medical service-mostly cancer-patients at hospital discharge.

Am J Med. 2011 Dec;124(12):1143-50

Authors: Fanikos J, Rao A, Seger AC, Piazza G, Catapane E, Chen X, Goldhaber SZ

Abstract
OBJECTIVE: Many hospitalized Medical Service patients remain at high risk for venous thromboembolism (VTE) after hospital discharge. Our aim was to compare the effect of the use or omission of extended pharmacologic VTE prophylaxis after hospital discharge among Medical Service patients on the incidence of symptomatic deep vein thrombosis (DVT) or pulmonary embolism (PE) over the ensuing 3 months.
METHODS: In this case-control study, we identified a case population of 461 patients for whom parenteral pharmacological VTE prophylaxis was prescribed to continue after discharge and matched them according to age, sex, and VTE risk score to a control group of 922 patients for whom VTE prophylaxis was not continued after discharge.
RESULTS: The primary endpoint of symptomatic DVT or PE at 90 days occurred in 5.0% of patients receiving extended prophylaxis compared with 4.3% of patients who received no prophylaxis after discharge (P=.58). Fewer patients were alive at 90 days in patients receiving extended pharmacologic VTE prophylaxis, compared with those who received no prophylaxis after discharge (56.8% vs 68.4%, P <.001). Major bleeding, defined as those events requiring blood transfusion, medical, or surgical intervention, occurred more frequently in patients receiving extended VTE prophylaxis after discharge than in those patients who received no prophylaxis after discharge (3.9% vs 1.9%, P=.03).
CONCLUSION: Extended pharmacologic thromboprophylaxis in high-risk Medical Service patients did not reduce symptomatic DVT and PE in the ensuing 90 days after hospital discharge. There was a higher incidence of all-cause death and major bleeding episodes in patients receiving extended prophylaxis. Our observations do not support the routine use of extended VTE prophylaxis in Medical Service patients. Further research is needed to identify patients who may benefit from extended pharmacologic VTE prophylaxis and those who may have too great a bleeding risk.

PMID: 22114828 [PubMed - in process]

Preoperative Thienopyridine Use and Outcomes after Surgery: A Systematic Review.

Am J Med. 2011 Nov 11;

Authors: Au AG, Majumdar SR, McAlister FA

Abstract
BACKGROUND: Although studies have demonstrated excess risk of ischemic events if aspirin is withheld preoperatively, it is unclear whether preoperative thienopyridine use influences postoperative outcomes. METHODS: We conducted a systematic review of 37 studies (31 cardiac and 6 noncardiac surgery, 3 randomized, 34 observational) comparing postoperative outcomes in patients who were versus were not exposed to thienopyridine in the 5 days before surgery. RESULTS: Exposure to thienopyridine in the 5 days preceding surgery (compared with no exposure) was not associated with any reduction in postoperative myocardial infarction (23 studies, 12,872 patients, 3.4% vs 3.0%, odds ratio [OR] 0.98; 95% confidence interval [CI], 0.72-1.34), but was associated with increased risks of stroke (16 studies, 10,265 patients, 1.9% vs 1.4%, OR 1.54; 95% CI, 1.08-2.20), reoperation for bleeding (32 studies, 19,423 patients, 4.3% vs 1.8%, OR 2.62; 95% CI, 1.96-3.49), and all-cause mortality (28 studies, 22,990 patients, 3.7% vs 2.6%, OR 1.38; 95% CI, 1.13-1.69). Results were identical when analyses were restricted to long-term users of thienopyridines who continued versus held the medication in the 5 days before surgery. Although all associations were similar in direction for the subset of patients undergoing noncardiac surgery, 97% of the outcome data in this meta-analysis came from cardiac surgery trials. CONCLUSIONS: These data support withholding thienopyridines 5 days before cardiac surgery; there was insufficient evidence to make definitive recommendations for elective noncardiac surgery although the direction and magnitude of associations were similar.

PMID: 22079019 [PubMed - as supplied by publisher]

Thrombosis in Suspected Heparin-Induced Thrombocytopenia Occurs More Often With High Antibody Levels.

Am J Med. 2011 Nov 8;

Authors: Baroletti S, Hurwitz S, Conti NA, Fanikos J, Piazza G, Goldhaber SZ

Abstract
OBJECTIVE: The study objective was to determine whether higher antiplatelet factor 4 (PF4)/heparin antibody levels using an enzyme-linked immunosorbent assay are associated with more frequent thrombotic events in patients with clinically suspected heparin-induced thrombocytopenia. Heparin-induced thrombocytopenia is an immune-mediated adverse drug reaction. An enzyme-linked immunosorbent assay detects anti-PF4/heparin antibodies to support a suspected clinical diagnosis of heparin-induced thrombocytopenia. The utility of quantitative enzyme-linked immunosorbent assay results is uncertain. METHODS: Our single-centered study evaluated quantitative anti-PF4/heparin antibody levels using an enzyme-linked immunosorbent assay in consecutive hospitalized patients with a clinical suspicion of heparin-induced thrombocytopenia and positive anti-PF4/heparin antibody levels between July 2003 and December 2006. RESULTS: Overall, anti-PF4/heparin antibody values were available for 318 patients with clinically suspected heparin-induced thrombocytopenia. The median level was 0.85 optical density units (range 0.31-4.0). The overall rate of arterial or venous thrombosis was 23.3%. A 1-unit increase in anti-PF4/heparin antibody level was associated with an approximate doubling in the odds of thrombosis by 30 days (odds ratio, 1.9; 95% confidence interval, 1.5-2.6; P=.0001). The proportion of patients with pulmonary embolism increased with higher anti-PF4/heparin antibody levels. CONCLUSION: Higher levels of anti-PF4/heparin antibody are associated with increased thrombosis risk among patients with clinically suspected heparin-induced thrombocytopenia and might have clinical utility for prediction of true heparin-induced thrombocytopenia and the development of thrombosis.

PMID: 22075045 [PubMed - as supplied by publisher]

Risk of Thiazide-induced Hyponatremia in Patients with Hypertension.

Am J Med. 2011 Nov;124(11):1064-72

Authors: Leung AA, Wright A, Pazo V, Karson A, Bates DW

Abstract
BACKGROUND: Although hyponatremia is a well-recognized complication of treatment with thiazide diuretics, the risk of thiazide-induced hyponatremia remains uncertain in routine care.
METHODS: We conducted a retrospective cohort study using a multicenter clinical research registry to identify 2613 adult outpatients that were newly treated for hypertension between January 1, 2000 and December 31, 2005 at 2 teaching hospitals in Boston, Massachusetts, and followed them for up to 10 years.
RESULTS: Two hundred twenty patients exposed to ongoing thiazide therapy were compared with 2393 patients who were not exposed. In the exposed group, 66 (30%) developed hyponatremia (sodium ?130 mmol/L). The adjusted incidence rate of hyponatremia was 140 cases per 1000 person-years for patients treated with thiazides, compared with 87 cases per 1000 person-years in those without thiazides. Patients exposed to thiazides were more likely to develop hyponatremia (adjusted incidence rate ratio, 1.61; 95% confidence interval [CI], 1.15-2.25). There was no significant difference in the risk of hospitalizations associated with hyponatremia (adjusted rate ratio, 1.04; 95% CI, 0.46-2.32) or mortality (adjusted rate ratio, 0.41; 95% CI, 0.12-1.42). The number needed to harm (to result in one excess case of incident hyponatremia in 5 years) was 15.02 (95% CI, 7.88-160.30).
CONCLUSIONS: Approximately 3 in 10 patients exposed to thiazides who continue to take them develop hyponatremia.

PMID: 22017784 [PubMed - in process]

Hypoglycemia-associated Mortality Is Not Drug-associated but Linked to Comorbidities.

Am J Med. 2011 Nov;124(11):1028-35

Authors: Boucai L, Southern WN, Zonszein J

Abstract
OBJECTIVE: Although tight glucose control is used widely in hospitalized patients, there is concern that medication-induced hypoglycemia may worsen patient outcomes. We sought to determine if the mortality risk associated with hypoglycemia in hospitalized noncritically ill patients is linked to glucose-lowering medications (drug-associated hypoglycemia) or merely an association mediated by comorbidities (spontaneous hypoglycemia).
METHODS: A retrospective cohort of patients admitted to the general wards of an academic center during 2007 was studied. The in-hospital mortality risk of a hypoglycemic group (at least 1 blood glucose?70 mg/dL) was compared with that of a normoglycemic group using survival analysis. Stratification by subgroups of patients with spontaneous and drug-associated hypoglycemia was performed.
RESULTS: Among 31,970 patients, 3349 (10.5%) had at least 1 episode of hypoglycemia. Patients with hypoglycemia were older, had more comorbidities, and received more antidiabetic agents. Hypoglycemia was associated with increased in-hospital mortality (hazard ratio [HR], 1.67; 95% confidence interval [CI], 1.33-2.09; P<.001). However, this greater risk was limited to patients with spontaneous hypoglycemia (HR, 2.62; 95% CI, 1.97-3.47; P<.001) and not to patients with drug-associated hypoglycemia (HR, 1.06; 95% CI, 0.74-1.52; P=.749). After adjustment for patient comorbidities, the association between spontaneous hypoglycemia and mortality was eliminated (HR, 1.11; 95% CI, 0.76-1.64; P=.582).
CONCLUSION: Drug-associated hypoglycemia was not associated with increased mortality risk in patients admitted to the general wards. The association between spontaneous hypoglycemia and mortality was eliminated after adjustment for comorbidities, suggesting that hypoglycemia may be a marker of disease burden rather than a direct cause of death.

PMID: 22017781 [PubMed - in process]

Cardiac amyloidosis: a practical approach to diagnosis and management.

Am J Med. 2011 Nov;124(11):1006-15

Authors: Kapoor P, Thenappan T, Singh E, Kumar S, Greipp PR

Abstract
Cardiac amyloidosis, the primary determinant of prognosis in systemic amyloidoses, is characterized by infiltration of myocardium by amyloid protein resulting in cardiomyopathy and conduction disturbances. Cardiac involvement is primarily encountered in immunoglobulin (AL) and transthyretin-associated (hereditary/familial and senile) amyloidoses. Although the latter variants could be indolent, untreated AL amyloidosis with clinical cardiac involvement is a rapidly fatal disease. The management decisions of cardiac amyloidosis are based on the underlying cause. Although treatment of senile systemic amyloidosis is largely supportive, the therapeutic approaches for AL amyloidosis include chemotherapy, autologous stem cell transplantation, and, rarely, cardiac transplantation. The familial variant is potentially curable with a liver±cardiac transplantation. This narrative review outlines a practical approach to these challenging diagnoses in the face of rapidly evolving management strategies.

PMID: 22017778 [PubMed - in process]

Oxygen therapy for acute myocardial infarction-then and now. A century of uncertainty.

Am J Med. 2011 Nov;124(11):1000-5

Authors: Kones R

Abstract
For about 100 years, inhaled oxygen has been administered to all patients suspected of having an acute myocardial infarction. The basis for this practice was the belief that oxygen supplementation raised often-deficient arterial oxygen content to improve myocardial oxygenation, thereby reducing infarct size. This assumption is conditional and not evidence-based. While such physiological changes may pertain in some patients who are hypoxemic, considerable data suggest that oxygen therapy may be detrimental in others. Acute oxygen therapy may raise blood pressure and lower cardiac index, heart rate, cardiac oxygen consumption, and blood flow in the cerebral and renal beds. Oxygen also may lower capillary density and redistribute blood in the microcirculation. Several reports now confirm that these changes occur in humans. In patients with both acute coronary syndromes and stable coronary disease, oxygen administration may constrict the coronary vessels, lower myocardial oxygen delivery, and may actually worsen ischemia. There are no large, contemporary, randomized studies that examine clinical outcomes after this intervention. Hence, this long-accepted but potentially harmful tradition urgently needs reevaluation. Clinical guidelines appear to be changing, favoring use of oxygen only in hypoxemic patients, and then cautiously titrating to individual oxygen tensions.

PMID: 22017777 [PubMed - in process]