HMGB-1 Protein Best Predictor of CF Complications

In a longitudinal study of patients with cystic fibrosis (CF), researchers at the University of Utah found that among the sputum biomarkers measured, only high mobility group box-1 (HMGB-1) protein was associated with future acute pulmonary exacerbations (APE) and time to lung transplantation or death (PLoS One 2012;7:e42748). In comparison to percent predicted forced expiratory volume in 1 second (FEV1%) and all other biomarkers alone or in combination, sputum HMGB-1 measurement was a better predictor of subsequent APE and time-to-first APE.

The investigators conducted the study under the premise that biomarkers that predict clinical outcomes might also identify causal mechanisms for airway disease in CF, help determine quickly the efficacy of new therapies, and distinguish patients most in need of urgent interventions.

The study involved 97 adult CF patients recruited between 2004–2007 and followed a median of 5.9 years. In addition to HMGB-1 the researchers measured numerous other sputum biomarkers, including granulocyte macrophage colony stimulating factor (GM-CSF), interleukin-1β, 2, 5, 6, 8, 10, 12p40, 13, and 17, and tumor necrosis factor-α, among others.

The authors conducted five different statistical analyses, including biomarker measurements and concurrent clinical status, biomarker behavior with change in patient status from stable to APE, relationship of biomarkers with APE-associated clinical changes, prediction of future APE, and HMGB-1 as an independent predictor of lung transplantation or death. After all these analyses, HMGB-1 proved to be the key biomarker; however, at APE onset, GM-CSF was significantly associated with APE-associated declines in lung function.

HDL-C SNP Carriers Not at Reduced Risk for MI

A large international consortium of researchers found that polymorphisms related to plasma LDL cholesterol (LDL-C) were consistently associated with risk of myocardial infarction (MI), whereas the same association did not hold for variants related to plasma HDL cholesterol (HDL-C) (Lancet 2012;380:572–80). The findings suggest that some genetic mechanisms that raise HDL-C do not lower risk of MI; hence lifestyle or pharmaceutical interventions that raise plasma HDL-C can't be assumed to lower risk of MI.

In a case-control design, the investigators first tested lipid-associated SNPs individually for association with risk of MI. Next, they tested two instruments, a single SNP, LIPG Asn396Ser, which is related to plasma HDL-C, and a genetic score consisting of 14 common SNPs exclusively associated with HDL-C. They tested LIPG Asn396Ser in 20,913 MI cases and 95,407 controls from several different studies, and the genetic score in 12,482 MI cases and 41,331 controls. In addition, they tested a genetic score of 13 common SNPs associated exclusively with LDL-C.

The authors found that in comparison to non-carriers, subjects who carried the LIPG 396Ser allele had higher HDL-C but similar levels of other lipid and non-lipid risk factors for MI. The investigators estimated that carrying this allele should decrease risk of MI by 13%, but found it did not, as individuals with this allele had an odds ratio of 0.99. Observational epidemiology studies indicate that a 1 standard deviation (SD) increase in HDL-C is associated with reduced risk of MI; however, the researchers found that a 1 SD increase in HDL-C due to genetic score was not associated with risk of MI. In contrast, estimates from observational epidemiology suggest that a 1 SD increase in LDL-C is associated with an increased risk of MI, with an odds ratio of 1.54. This risk concurred with the risk from the authors' genetic score.

Preoperative Hyponatremia Predicts Postoperative Complications

Preoperative hyponatremia, even to a mild degree, is common and predicts postoperative morbidity and mortality, even in relatively healthy patients, and in those undergoing nonemergency surgery (Arch Intern Med doi:10.1001/archinternmed.2012.3992). The findings suggest that even mild changes in serum sodium are not inconsequential and should not be ignored. In addition, whenever possible, the underlying cause of hyponatremia should be uncovered.

The authors assembled a cohort of patients from the American College of Surgeons National Surgical Quality Improvement Program. In all, they found data from 964,263 patients who were at least 18 years old, underwent any major surgery between 2005–2010, and in whom preoperative sodium measurements had been recorded. Of these, 75,423 (7.8%) had hyponatremia, defined as sodium <135 mEq/L. In comparison to patients with normal baseline sodium levels, defined as 135–144 mEq/L, those with hyponatremia had an adjusted odds ratio of 1.59 for 30-day mortality, 1.21 for perioperative major coronary events, 1.24 for wound infections, and 1.17 for pneumonia. The excess risk was present even in patients with mild hyponatremia, defined as 130–134 mEq/L. After controlling for all the covariates to account for differences in case mix, the investigators also found hyponatremia to be associated with a median 1 day longer hospitalization.

The researchers noted that controversy exists as to whether hyponatremia is a marker or a mediator of mortality and other adverse events, and called for further studies to determine whether correcting the condition preoperatively will mitigate risks.

Elevated RF Confers Long-term Risk of RA in Healthy Individuals

Healthy individuals in a general population with elevated rheumatoid factor (RF) have up to 26-fold greater long-term risk of rheumatoid arthritis (RA), and up to 32% 10-year absolute risk of RA (BMJ 2012;345:e5244). These findings could lead to revision of RA clinical practice guidelines to suggest that depending on RF test results, early referral to a rheumatologist or arthritis clinic might be warranted.

This prospective cohort study involved 9,712 adults without RA at enrollment. Subjects provided blood samples between 1981–1983, which were frozen at -20°C. The participants were followed until 2010, when RF concentrations were measured from the 1981–1983 samples. During 187,654 person years of follow-up, 183 individuals developed RA. Median age at diagnosis was 70 years and the median time from providing a blood sample to developing RA was 15 years for those with RF levels <25 IU/mL, 12 years for those with RF concentrations 25–50 IU/mL, and 7 years for those with RF levels of either 50.1–100 IU/mL or >100 IU/mL.

The cumulative incidence of RA increased with increasing RF levels. In comparison to individuals with RF levels <25 IU/mL, multivariate adjusted hazard ratios for RA were 3.6 for RF levels 25–50 IU/mL, 6.0 for RF concentrations 50.1–100 IU/mL, and 26 for RF levels >100. The highest absolute 10-year risk of RA was found in women 50–69 years old who smoked and had RF concentrations >100 IU/mL. The lowest risk was in men at least 70 years old with RF levels <25 IU/mL, irrespective of smoking status.