Sample size considerations using mathematical models: an example with Chlamydia trachomatis infection and its sequelae pelvic inflammatory disease.

BACKGROUND The success of an intervention to prevent the complications of an infection is influenced by the natural history of the infection. Assumptions about the temporal relationship between infection and the development of sequelae can affect the predicted effect size of an intervention and the sample size calculation. This study investigates how a mathematical model can be used to inform sample size calculations for a randomised controlled trial (RCT) using the example of Chlamydia trachomatis infection and pelvic inflammatory disease (PID). METHODS We used a compartmental model to imitate the structure of a published RCT. We considered three different processes for the timing of PID development, in relation to the initial C. trachomatis infection: immediate, constant throughout, or at the end of the infectious period. For each process we assumed that, of all women infected, the same fraction would develop PID in the absence of an intervention. We examined two sets of assumptions used to calculate the sample size in a published RCT that investigated the effect of chlamydia screening on PID incidence. We also investigated the influence of the natural history parameters of chlamydia on the required sample size. RESULTS The assumed event rates and effect sizes used for the sample size calculation implicitly determined the temporal relationship between chlamydia infection and PID in the model. Even small changes in the assumed PID incidence and relative risk (RR) led to considerable differences in the hypothesised mechanism of PID development. The RR and the sample size needed per group also depend on the natural history parameters of chlamydia. CONCLUSIONS Mathematical modelling helps to understand the temporal relationship between an infection and its sequelae and can show how uncertainties about natural history parameters affect sample size calculations when planning a RCT

Serum concentration of HDL particles predicts mortality in acute heart failure patients

Clinical studies have shown that assessing circulating concentrations of high-density lipoprotein (HDL) particles by nuclear magnetic resonance (NMR) spectroscopy is superior to HDL-cholesterol in predicting cardiovascular risk. We tested the hypothesis that circulating concentrations of HDL particles predict 3-month mortality of patients with acute heart failure (AHF). Out of 152 included patients, 52% were female, additionally the mean patient age was 75.2 ± 10.3 years, and three-month mortality was 27%. Serum lipoprotein profile at admission was determined by NMR spectroscopy. Univariate logistic regression analyses revealed a significant inverse association of total (odds ratio (OR) 0.38 per 1-SD increase, 95% confidence interval (CI) 0.23-0.60, p < 0.001) and small HDL particle concentrations (OR 0.35 per 1-SD increase, 95% CI 0.19-0.60, p < 0.001) with 3-month mortality, whereas concentrations of large HDL particles (p = 0.353) or HDL-cholesterol (p = 0.107) showed no significant association. After adjustment for age, sex, mean arterial pressure, low-density lipoprotein cholesterol, glomerular filtration rate, urea, and N-terminal pro-brain natriuretic peptide, both the total and small HDL particle concentrations remained significantly associated with 3-month mortality. Based on our results, we conclude that total and small HDL particle concentrations strongly and independently predict 3-month mortality in AHF patients

Serum concentrations of Citrate, Tyrosine, 2- and 3- Hydroxybutyrate are associated with increased 3-month mortality in acute heart failure patients

Considering the already established relationship between the extent of the metabolic dysfunction and the severity of heart failure (HF), it is conceivable that the metabolomic profile of the serum may have a prognostic capacity for 3-month mortality in acute heart failure (AHF). Out of 152 recruited patients, 130 serum samples were subjected to the metabolomic analyses. The 3-month mortality rate was 24.6% (32 patients). Metabolomic profiling by nuclear magnetic resonance spectroscopy found that the serum levels of 2-hydroxybutyrate (2-HB), 3-hydoxybutyrate (3-HB), lactate, citrate, and tyrosine, were higher in patients who died within 3 months compared to those who were alive 3 months after onset of AHF, which was confirmed by univariable logistic regression analyses (p = 0.009, p = 0.005, p = 0.008, p<0.001, and p<0.001, respectively). These associations still remained significant for all tested metabolites except for lactate after adjusting for established prognostic parameters in HF. In conclusion, serum levels of 2-HB, 3-HB, tyrosine, and citrate measured at admission are associated with an increased 3-month mortality rate in AHF patients and might thus be of prognostic value in AHF

Metabolic syndrome modulates association between endothelial lipase and lipid/lipoprotein plasma levels in acute heart failure patients

We hypothesised that the established association of endothelial lipase (EL) plasma levels with atherogenic lipid profile is altered in acute heart failure (AHF) and additionally affected by overlapping metabolic syndrome (MetS). We examined the association of EL plasma levels and lipid/lipoprotein plasma levels in AHF patients without and with overlapping MetS. The study was performed as a single-centre, observational study on 152 AHF patients, out of which 85 had overlapping MetS. In the no-MetS group, EL plasma levels were significantly positively correlated with plasma levels of atherogenic lipids/lipoproteins, including total cholesterol, low-density lipoprotein (LDL)-cholesterol, total LDL particles and triglycerides, but also with plasma levels of antiatherogenic high-density lipoprotein (HDL)-cholesterol, total HDL particles and small HDL particles. In the MetS group, EL plasma levels were positively correlated with triglyceride and small LDL-particle levels, and significantly negatively correlated with plasma levels of large HDL particles as well as with LDL- and HDL-particle size, respectively. EL- and lipid/lipoprotein- plasma levels were different in the no-MetS patients, compared to MetS patients. The association of EL with atherogenic lipid profile is altered in AHF and additionally modified by MetS, which strongly modulates EL- and lipid/lipoprotein-plasma levels in AHF

Serum concentrations of free fatty acids are associated with 3-month mortality in acute heart failure patients

Background: Plasma free fatty acids (FFA) are higher in heart failure (HF) patients compared to healthy controls. Considering that the extent of FFA elevation in HF might mirror the severity of HF, we hypothesized that the serum levels of FFA may be a useful prognostic indicator for 3-month mortality in acute heart failure (AHF). ----- Methods: We analyzed the serum samples of AHF patients obtained at admission to the emergency department. Serum levels of FFA were analyzed using an enzymatic reagent on an automatic analyzer. ----- Results: Out of 152 included AHF patients that were originally included, serum samples of 132 patients were available for the quantification of FFA. Of these, 35 (26.5%) died within 3 months of onset of AHF. These patients had significantly higher serum levels of FFA compared to AHF patients who were alive 3 months after onset of AHF. Univariable logistic regression analyses showed a significant positive association of FFA levels with 3-month mortality (odds ratio [OR] 2.76 [95% confidence interval 1.32-6.27], p = 0.010). Importantly, this association remained significant after adjusting for age and sex, as well as for further clinical and laboratory parameters that showed a significant association with 3-month mortality in the univariate analyses. ----- Conclusions: We conclude that the admission serum levels of FFA are associated with 3-month mortality in AHF patients. Therefore, measurements of circulating FFA levels may help identifying high-risk AHF patients

Metrics of high-density lipoprotein function and hospital mortality in acute heart failure patients

OBJECTIVE: The functionality of high-density lipoprotein (HDL) is impaired in chronic ischaemic heart failure (HF). However, the relationship between HDL functionality and outcomes in acute HF (AHF) has not been studied. The present study investigates whether the metrics of HDL functionality, including HDL cholesterol efflux capacity and HDL-associated paraoxonase (PON)-1 arylesterase (AE) activity are associated with hospital mortality in AHF patients. ----- METHODS AND RESULTS: The study was performed as a prospective, single-centre, observational research on 152 patients, defined and categorised according to the ESC and ACCF/AHA Guidelines for HF by time of onset, final clinical presentation and ejection fraction. The mean age of the included patients (52% female) was 75.2 years (SD 10.3) and hospital mortality was 14.5%. HDL cholesterol efflux capacity was examined by measuring the capacity of apoB depleted serum to remove tritium-labelled cholesterol from cultured macrophages. The AE activity of the HDL fraction was examined by a photometric assay. In a univariable regression analysis, low cholesterol efflux, but not AE activity, was significantly associated with hospital mortality [odds ratio (OR) 0.78, 95% confidence interval (CI) 0.64-0.96, p = 0.019]. In multivariable analysis progressively adjusting for important clinical and laboratory parameters the association obtained for cholesterol efflux capacity and hospital mortality by univariable analysis, despite a stable OR, did not stay significant (p = 0.179). ----- CONCLUSION: Our results suggest that HDL cholesterol efflux capacity (but not AE activity) contributes to, but is not an independent risk factor for, hospital mortality in AHF patients. Larger studies are needed to draw firm conclusions

A New Synthetic Conduit for the Treatment of Peripheral Nerve Injuries

Background Peripheral nerve defects (PND) often cause lifelong physical disability, and the available treatment options are often not satisfactory. PND are usually bridged with an autologous nerve transplant or a nerve guidance conduit (NGC), when coaptation as preferred technique is not possible. The aim of this experimental study was to determine the effectiveness of a novel NGC for regeneration in the treatment of PND. Materials and methods A conduit made of gelatin with an innovative interior structure was tested for the repair of a 6-mm gap versus direct microsurgical suture repair without gap. Results We found that bridging the defect with this conduit was as effective as direct microsurgical coaptation without a defect. Conclusions This nerve conduit, effective in bridging neural defects, appears as an alternative to autologous nerve grafts, avoiding the problems related to nerve graft harvesting, host–donor differences in diameter, mismatches in number and pattern of fascicles, cross-sectional shape and area, and morbidity of the donor area

Serum concentrations of asymmetric and symmetric dimethylarginine are associated with mortality in acute heart failure patients

BACKGROUND: Serum concentrations of asymmetric (ADMA) and symmetric (SDMA) dimethylarginine are established predictors of total and cardiovascular mortality. However, the predictive capacity of ADMA and SDMA for hospital and 3-months mortality of patients with acute heart failure (AHF) is unknown. ----- METHODS & RESULTS: Out of 152 included AHF patients, 79 (52%) were female, and the mean patient age was 75.2 ± 10.3 years. Hospital and three-month mortality rates were 14.5% and 27.4%, respectively. Serum ADMA and SDMA levels at admission, determined by reversed phase high performance liquid chromatography, were higher in patients having at least one of the three signs implying venous volume overload (enlarged liver, ascites, peripheral edema), a consequence of right-sided heart failure, compared to patients without those signs. Univariable logistic regression analyses revealed a significant positive association of ADMA and SDMA concentrations with hospital mortality [odds ratio (OR) and 95% confidence interval (CI) per standard deviation (SD) increase: 2.22 (1.37-3.79), p = 0.002, and 2.04 (1.34-3.18), p = 0.001, respectively], and 3-months mortality [2.06 (1.36-3.26), p = 0.001, and 2.52 (1.67-4.04), p < 0.001, respectively]. These associations remained significant after adjusting for age, sex, mean arterial pressure, low-density lipoprotein cholesterol, glomerular filtration rate, and N-terminal pro-brain natriuretic peptide. ----- CONCLUSIONS: We conclude that ADMA and SDMA concentrations are associated with hospital and 3-month mortality and are increased by venous volume overload in AHF patients

Germline mutations in the DNA damage response genes BRCA1, BRCA2, BARD1 and TP53 in patients with therapy related myeloid neoplasms

Therapy related myeloid neoplasms (t-MNs) are complex diseases originating from an interplay between exogenous toxicities and a susceptible organism. It has been hypothesised that in a subset of cases t-MNs develop in the context of hereditary cancer predisposition syndromes

Acute heart failure developed as worsening of chronic heart failure is associated with increased mortality compared to de novo cases

Acute heart failure (AHF) emerges either de novo or from worsening of chronic heart failure (CHF). The aim of the present study was to evaluate the association between worsening of CHF and mortality in AHF patients. Out of 152 included AHF patients, 47 (30.9%) were de novo AHF patients and 105 (69%) were AHF patients with worsening of CHF. The proportion dying in hospital (19.0% vs. 4.3%, p = 0.023) and within 3 months after hospitalization (36.6% vs. 6.7%, p < 0.001) was significantly higher in AHF patients with worsening of CHF. Logistic regression analyses also showed a significant positive association of AHF emerging as worsening of CHF with hospital mortality [odds ratio (OR) and 95% confidence interval (CI): 5.29 (1.46-34.10), p = 0.029] and 3-month mortality [8.09 (2.70-35.03), p = 0.001]. While the association with hospital mortality was no longer significant after adjusting for comorbidities and clinical as well as laboratory parameters known to be associated with mortality in heart failure patients, the association with 3-month mortality remained significant. We conclude that compared to de novo AHF, AHF evolved from worsening of CHF is a more severe condition and is associated with increased mortality