Abstract Background In the diagnostic reasoning process medical students and novice physicians need to be made aware of the diagnostic values of the clinical findings (including history, signs, and symptoms) to make an appropriate diagnostic decision. Diagnostic reasoning has been understood in light of two paradigms on clinical reasoning: problem solving and decision making. They advocate the reasoning strategies used by expert physicians and the statistical models of reasoning, respectively. Evidence-based medicine (EBM) applies decision theory to the clinical diagnosis, which can be a challenging topic in medical education. This theoretical article tries to compare evidence-based diagnosis with expert-based strategies in clinical diagnosis and also defines a novel concept of category-oriented likelihood ratio (LR) to propose a new model combining both aforementioned methods. Discussion Evidence-based medicine advocates the use of quantitative evidence to estimate the probability of diseases more accurately and objectively; however, the published evidence for a given diagnosis cannot practically be utilized in primary care, especially if the patient is complaining of a nonspecific problem such as abdominal pain that could have a long list of differential diagnoses. In this case, expert physicians examine the key clinical findings that could differentiate between broader categories of diseases such as organic and non-organic disease categories to shorten the list of differential diagnoses. To approach nonspecific problems, not only do the experts revise the probability estimate of specific diseases, but also they revise the probability estimate of the categories of diseases by using the available clinical findings. Summary To make this approach analytical and objective, we need to know how much more likely it is for a key clinical finding to be present in patients with one of the diseases of a specific category versus those with a disease not included in that category. In this paper, we call this value category-oriented LR.

Background

Serum ferritin, frequently used as a marker of iron status in individuals with chronic kidney disease, is also an inflammatory marker. The concurrent combination of high serum ferritin and low iron saturation ratio (ISAT) usually poses a diagnostic dilemma. We hypothesized that serum ferritin > or =500 ng/ml, especially in the seemingly paradoxical presence of ISAT level <25%, is more strongly associated with inflammation than with iron in maintenance hemodialysis (MHD) patients.

Design, setting, and participants

In 789 MHD patients in the Los Angeles area, the association of serum ferritin > or =500 ng/ml with inflammatory markers, including IL-6 (IL-6) and C-reactive protein levels, and malnutrition-inflammation score (MIS) was examined.

Results

After multivariate adjustment for case-mix and other measures of malnutrition-inflammation complex, MHD patients with serum ferritin > or =500 ng/ml and ISAT <25% had higher odds ratio for serum C-reactive protein > or =10 mg/L. The area under the receiver operating characteristic curves for the continuum of ISAT and IL-6 in detecting a serum ferritin > or =500 ng/ml were identical (0.57 versus 0.56, P = 0.7). The combination of IL-6 with ISAT yielded a higher area under the receiver operating characteristic curve (0.61) than either ISAT or IL-6 alone (P = 0.03 and P = 0.02, respectively).

Conclusion

In MHD patients, ferritin values above 500 ng/ml, especially in paradoxical conjunction with low ISAT, are associated with inflammation. Strategies to dissociate inflammation from iron metabolism to mitigate the confounding impact of inflammation on iron and to improve iron treatment responsiveness may improve anemia management in chronic kidney disease.

Background: Underweight chronic obstructive pulmonary disease (COPD) patients with involuntary weight loss have a poor prognosis; no effective therapy is currently available. We conducted the first clinical trial seeking to determine whether combination therapy with an appetite stimulant and an anabolic steroid would have beneficial effects on body composition for patients with COPD cachexia. Methods: We conducted a 12-week pilot study in which 4 men and 5 women (age 64±10 y, forced expiratory volume in 1 second [FEV₁] 31±9 %pred., body mass index [BMI] 18±3 kg/m²) with low-normal testosterone levels (average 532±45ng/dl in men and 12.4±5.3ng/dl in women) and weight loss ≥10 lbs over the previous year were treated with oral megestrol acetate 800mg/day plus weekly testosterone enanthate injections, initially 125 mg in men and 40 mg in women, with doses subsequently adjusted targeting circulating nadir testosterone levels of 850 and 300 ng/dl, respectively. Results: On treatment, nadir testosterone level increases averaged 160±250 ng/dl (NS) in men and 322±49 (p<0.001) ng/dl in women. Body weight increased in all individuals, with average end-intervention weight gain of 3.1±2.2 kg (p<0.005). Two women and 2 men had COPD exacerbations and did not complete the 12-week study. In the 5 individuals who completed, dual energy x ray absorptiometry (DEXA) scans revealed an average 2.0±1.5 kg lean mass and 2.3±1.7 kg fat mass increase (each p<0.05). No adverse effects of treatment were detected. Conclusions: Combination therapy reversed the trajectory of involuntary weight loss and increased lean mass in cachectic COPD patients. Though the interventions were apparently well tolerated, participant drop-out rate was high. Larger randomized placebo-controlled long-term studies with functional outcomes are needed.

Background

In patients receiving maintenance hemodialysis (MHD), a low serum prealbumin is an indicator of protein-energy wasting.

Objective

We hypothesized that baseline serum prealbumin correlates independently with health-related quality of life (QoL) and death and that its change over time is a robust mortality predictor.

Design

Associations and survival predictability of serum prealbumin at baseline and its changes over 6 mo were examined in a 5-y (2001-2006) cohort of 798 patients receiving MHD.

Results

Patients with serum prealbumin >or= 40 mg/dL had greater mid-arm muscle circumference but lower percentage of total body fat. Both serum interleukin-6 and dietary protein intake correlated independently with serum prealbumin. Measures of QoL indicated better physical health, physical function, and functionality with higher prealbumin concentrations. Although baseline prealbumin was not superior to albumin in predicting survival, in both all and normoalbuminemic (albumin >or= 3.5 g/dL; n = 655) patients, prealbumin < 20 mg/dL was associated with higher death risk in adjusted models, but further adjustments for inflammatory cytokines mitigated the associations. In 412 patients with baseline prealbumin between 20 and 40 mg/dL whose serum prealbumin was remeasured after 6 mo, a >or=10-mg/dL fall resulted in a death hazard ratio of 1.37 (95% CI: 1.02, 1.85; P = 0.03) after adjustment for baseline measures, including inflammatory markers.

Conclusions

Even though baseline serum prealbumin may not be superior to albumin in predicting mortality in MHD patients, prealbumin concentrations <20 mg/dL are associated with death risk even in normoalbuminemic patients, and a fall in serum prealbumin over 6 mo is independently associated with increased death risk.

Background

CD14 is a key molecule in innate immunity that mediates cell activation and signaling in response to endotoxin and other bacterial wall-derived components. CD14 protein exists in soluble (sCD14) and membrane-bound forms. The correlates of sCD14 in persons undergoing long-term hemodialysis (HD) therapy are not known. We hypothesized that increased sCD14 levels in HD patients are associated with proinflammatory cytokine activation and increased mortality.

Study design

Cohort study.

Setting & participants

310 long-term HD patients who participated in the Nutritional and Inflammatory Evaluation in Dialysis (NIED) Study, a cohort derived from a pool of more than 3,000 HD outpatients during 5 years in 8 DaVita maintenance dialysis facilities in the South Bay Los Angeles, CA, area.

Predictors

sCD14 levels in serum.

Outcomes

33-month mortality.

Results

Mean sCD14 level was 7.24 +/- 2.45 microg/mL. Tumor necrosis factor alpha level was the strongest correlate of sCD14 level (r = +0.24; P < 0.001), followed by interleukin 6 level (r = +0.18; P = 0.002), serum ferritin level (r = +0.21; P < 0.001), total iron-binding capacity (r = -0.19; P < 0.001), body mass index (r = -0.15; P = 0.008), vintage (r = +0.14; P = 0.01), low-density lipoprotein cholesterol level (r = +0.13; P = 0.03), and body fat (r = -0.11; P = 0.06). During the 33-month follow-up, 71 (23%) patients died. Multivariable Cox proportional analysis adjusted for case-mix and other nutritional and inflammatory confounders, including serum tumor necrosis factor alpha, C-reactive protein, and interleukin 6 levels, showed that compared with the lowest sCD14 tertile, sCD14 levels in the third tertile (>7.8 microg/mL) were associated with greater death risk (hazard ratio, 1.94; 95% confidence interval, 1.01 to 3.75; P = 0.04).

Limitations

Survivor bias in combined incident/prevalent studies.

Conclusions

Increased sCD14 level is related positively to markers of inflammation and negatively to nutritional status and is an independent predictor of mortality in long-term HD patients. Additional studies are needed to examine the usefulness of sCD14 level in risk stratification and the clinical decision-making process in HD patients.

Serum transferrin, estimated by total iron-binding capacity (TIBC), may be a marker of protein-energy wasting (PEW) in maintenance hemodialysis (MHD) patients. We hypothesized that low TIBC or its fall over time is associated with poor clinical outcomes. In 807 MHD patients in a prospective 5-year cohort, associations of TIBC and its changes over time with outcomes were examined after adjustment for case-mix and markers of iron stores and malnutrition-inflammation including serum interleukin-6, iron and ferritin. Patients with serum TIBC >or=250 mg/dl had higher body mass index, triceps and biceps skinfolds and mid-arm muscle circumference and higher serum levels of iron but lower ferritin and inflammatory markers. Some SF-36 quality of life (QoL) components were worse in the lowest and/or highest TIBC groups. Mortality was incrementally higher in lower TIBC levels (p-trend <0.001). Adjusted death hazard ratio was 1.75 (95% CI: 1.00-3.05, p = 0.05) for TIBC <150 compared to TIBC of 200-250 mg/dl. A fall in TIBC >20 mg/dl over 6 months was associated with a death hazard ratio of 1.57 (95% CI: 1.04-2.36, p = 0.03) compared to the stable TIBC group. Hence, low baseline serum TIBC is associated with iron deficiency, PEW, inflammation, poor QoL and mortality, and its decline over time is independently associated with increased death risk.