Assessment of adult formulas for glomerular filtration rate estimation in children

Background: Estimated glomerular filtration rate (eGFR) is an important diagnostic instrument in clinical practice. The National Kidney Foundation-Kidney Disease Quality Initiative (NKF-KDOQI) guidelines do not recommend using formulas developed for adults to estimate GFR in children; however, studies confirming these recommendations are scarce. The aim of our study was to evaluate the accuracy of the new Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula, the Modification of Diet in Renal Disease (MDRD) formula, and the Cockcroft-Gault formula in children with various stages of chronic kidney disease (CKD). Methods: A total of 550 inulin clearance (iGFR) measurements for 391 children were analyzed. The cohort was divided into three groups: group 1, with iGFR >90ml/min/1.73m2; group 2, with iGFR between 60 and 90 ml/min/1.73m2; group 3, with iGFR of <60 ml/min/1.73m2. Results: All formulas overestimate iGFR with a significant bias (p < 0.001), present poor accuracies, and have poor Spearman correlations. For an accuracy of 10%, only 11, 6, and 27% of the eGFRs are accurate when using the MDRD, CKD-EPI, and Cockcroft-Gault formulas, respectively. For an accuracy of 30%, these formulas do not reach the NKF-KDOQI guidelines for validation, with only 25, 20, and 70% of the eGFRs, respectively, being accurate. Conclusions: Based on our results, the performances of all of these formulas are unreliable for eGFR in children across all CKD stages and cannot therefore be applied in the pediatric population grou

Staphylococcus aureus from patients with chronic rhinosinusitis show minimal genetic association between polyp and non-polyp phenotypes

Background: Staphylococcus aureus has a high prevalence in chronic rhinosinusitis (CRS) patients and is suggested to play a more etiopathogenic role in CRS patients with nasal polyps (CRSwNP), a severe form of the CRS spectrum with poorer surgical outcomes. We performed a microbial genome-wide association study (mGWAS) to investigate whether S. aureus isolates from CRS patients have particular genetic markers associated with CRS with nasal polyps (CRSwNP) or CRS without nasal polyps (CRSsNP). Methods: Whole genome sequencing was performed on S. aureus isolates collected from 28 CRSsNP and 30 CRSwNP patients. A mGWAS approach was employed using large-scale comparative genomics to identify genetic variation within our dataset. Results: Considerable genetic variation was observed, with >90,000 single nucleotide polymorphisms (SNPs) sites identified. There was little correlation with CRS subtype based on SNPs and Insertion/Delection (Indels). One indel was found to significantly correlate with CRSwNP and occurred in the promoter region of a bacitracin transport system ATP-binding protein. Additionally, two variants of the highly variable superantigen-like (SSL) proteins were found to significantly correlate with each CRS phenotype. No significant association with other virulence or antibiotic resistance genes were observed, consistent with previous studies. Conclusion: To our knowledge this study is the first to use mGWAS to investigate the contribution of microbial genetic variation to CRS presentations. Utilising the most comprehensive genome-wide analysis methods available, our results suggest that CRS phenotype may be influenced by genetic factors other than specific virulence mechanisms within the S. aureus genome

Galen, divination, and the status of medicine

Galen's stories about his successes in predicting the development of an illness belong to the best-known anecdotes drawn from his writings. Brilliant pieces of self-presentation, they set Galen apart from his peers, who tried to cover up their ignorance by levelling accusations of magic and divination against their superior colleague. These accusations are usually interpreted as very real threats, as Roman law punished illicit magic and divination. Pointing out that Galen sometimes likes to present himself as a mantis and a prophet, others have suggested that the accusations against Galen and his own self-presentation indicate that the border line between medicine and religion was still fluid. Both approaches correctly draw attention to the social reality that the accusations betray: they suggest that Galen belongs to a group of healers of dubious standing that populated the empire and thus show that medicine did not have a monopoly on healing. Yet such a socio-historical approach may not be sufficient. For one thing, both explanations have their limitations. Regarding the former, it can be said that Augustus' prohibition of divination aimed at controlling prediction about the emperor and one can doubt that a widespread clampdown of all forms of divination ever was intended. A possible objection to the second view is that throughout his oeuvre Galen emphasizes his medicine as a rational undertaking, even as a science (episteme). If one takes his self-presentation as a mantis to be more than metaphorical and to indicate the not yet fully crystallized identity of medicine as a separate scientific discipline, then Galen's usual way of understanding his own craft as a science' is in need of explanation. Besides such possible objections, a different set of questions still needs to be asked: why precisely were accusations of practising magic and divination levelled against Galen and why do they recur so frequently in his writings? Why divination and not, say, poisoning

Pearls and perils of an implantable defibrillator trial using a common control: implications for the design of future studies

Abstract Aims Implantable defibrillators are considered life-saving therapy in heart failure (CHF) patients. Surprisingly, the recent Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) reached an opposing conclusion from that of numerous other trials about their survival benefit in patients with advanced CHF. A critical analysis of common control trial design may explain this paradoxical finding, with important implications for future studies. Methods and Results Common control trials compare several intervention groups to a single rather than separate control groups. Though potentially requiring fewer patients than trials using separate controls, variation in the common control group will influence all comparisons and creates correlations between findings. During subgroup analyses, this dependency of outcomes may increase belief in the presence of a real subgroup effect when, in fact, it should increase skepticism. For example, a high (r = 0.92), statistically unlikely (p = 0.052) correlation between comparisons was observed across the subgroups reported in SCD-HeFT. Such concordance between amiodarone and a defibrillator across subgroups was unexpected, given how much the effects of these treatments significantly differed from one another in the main study. This suggests the study's subgroup findings (specifically the absence of benefit from defibrillators in advanced CHF) were not necessarily a consequence of treatment; more likely, they resulted from variation in what the treatments were compared against, the common control. Conclusion Common control trials can be more efficient than other designs, but induce dependence between treatment comparisons and require cautious interpretation.</p

Unravelling socio-motor biomarkers in schizophrenia

We present novel, low-cost and non-invasive potential diagnostic biomarkers of schizophrenia. They are based on the ‘mirror-game’, a coordination task in which two partners are asked to mimic each other’s hand movements. In particular, we use the patient’s solo movement, recorded in the absence of a partner, and motion recorded during interaction with an artificial agent, a computer avatar or a humanoid robot. In order to discriminate between the patients and controls, we employ statistical learning techniques, which we apply to nonverbal synchrony and neuromotor features derived from the participants’ movement data. The proposed classifier has 93% accuracy and 100% specificity. Our results provide evidence that statistical learning techniques, nonverbal movement coordination and neuromotor characteristics could form the foundation of decision support tools aiding clinicians in cases of diagnostic uncertainty

Activating KIR Haplotype Influences Clinical Outcome Following HLA-Matched Sibling Hematopoietic Stem Cell Transplantation.

This is the peer reviewed version of the following article: Heatley, S. L., Mullighan, C. G., Doherty, K., Danner, S., O'Connor, G. M., Hahn, U., . . . Brooks, A. G. (2018). Activating KIR Haplotype Influences Clinical Outcome Following HLA-Matched Sibling Hematopoietic Stem Cell Transplantation. HLA, 92(2), which has been published in final form at https://doi.org/10.1111/tan.13327. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived VersionsNatural killer cells are thought to influence the outcome of hematopoietic stem cell transplant (HSCT), impacting on relapse, overall survival, graft versus host disease and the control of infection, in part through the complex interplay between the large and genetically diverse killer immunoglobulin-like receptor (KIR) family and their ligands. This study examined the relationship between KIR gene content and clinical outcomes including the control of opportunistic infections such as cytomegalovirus in the setting of human leucocyte antigen (HLA)-matched sibling HSCT in an Australian cohort. The presence of the KIR B haplotype which contain more activating receptors in the donor, in particular centromeric B haplotype genes (Cen-B), was associated with improved overall survival of patients with acute myeloid leukemia (AML) undergoing sibling HSCT and receiving myeloablative conditioning. Donor Cen-B haplotype was also associated with reduced acute graft versus host disease grades II-IV whereas donor telomeric-B haplotype was associated with decreased incidence of CMV reactivation. In contrast, we were not able to demonstrate a reduced rate of relapse when the donor had KIR Cen-B, however relapse with a donor Cen-A haplotype was a competing risk factor to poor overall survival. Here we show that the presence of donor activating KIR led to improved outcome for the patient, potentially through reduced relapse rates and decreased incidence of acute GvHD translating to improved overall survival

Investigation of the expression of the EphB4 receptor tyrosine kinase in prostate carcinoma

BACKGROUND: The EphB4 receptor tyrosine kinase has been reported as increased in tumours originating from several different tissues and its expression in a prostate cancer xenograft model has been reported. METHODS: RT-PCR, western blotting and immunohistochemical techniques were used to examine EphB4 expression and protein levels in human prostate cancer cell lines LNCaP, DU145 and PC3. Immunohistochemistry was also used to examine localisation of EphB4 in tissue samples from 15 patients with prostate carcinomas. RESULTS: All three prostate cancer cell lines expressed the EphB4 gene and protein. EphB4 immunoreactivity in vivo was significantly greater in human prostate cancers as compared with matched normal prostate epithelium and there appeared to be a trend towards increased expression with higher grade disease. CONCLUSION: EphB4 is expressed in prostate cancer cell lines with increased expression in human prostate cancers when compared with matched normal tissue. EphB4 may therefore be a useful anti-prostate cancer target

Implantable or External Defibrillators for Individuals at Increased Risk of Cardiac Arrest: Where Cost-Effectiveness Hits Fiscal Reality

Objcetives:  Implantable cardioverter defibrillators (ICDs) are highly effective at preventing cardiac arrest, but their availability is limited by high cost. Automated external defibrillators (AEDs) are likely to be less effective, but also less expensive. We used decision analysis to evaluate the clinical and economic trade-offs of AEDs, ICDs, and emergency medical services equipped with defibrillators (EMS-D) for reducing cardiac arrest mortality. Methods:  A Markov model was developed to compare the cost-effectiveness of three strategies in adults meeting entry criteria for the MADIT II Trial: strategy 1, individuals experiencing cardiac arrest are treated by EMS-D; strategy 2, individuals experiencing cardiac arrest are treated with an in-home AED; and strategy 3, individuals receive a prophylactic ICD. The model was then used to quantify the aggregate societal benefit of these three strategies under the conditions of a constrained federal budget. Results:  Compared with EMS-D, in-home AEDs produced a gain of 0.05 quality-adjusted life-years (QALYs) at an incremental cost of $5225 ($104,500 per QALY), while ICDs produced a gain of 0.90 QALYs at a cost of $114,660 ($127,400 per QALY). For every $1 million spent on defibrillators, 1.7 additional QALYs are produced by purchasing AEDs (9.6 QALYs/$million) instead of ICDs (7.9 QALYs/$million). Results were most sensitive to defibrillator complication rates and effectiveness, defibrillator cost, and adults’ risk of cardiac arrest. Conclusions:  Both AEDs and ICDs reduce cardiac arrest mortality, but AEDs are significantly less expensive and less effective. If financial constraints were to lead to rationing of defibrillators, it might be preferable to provide more people with a less effective and less expensive intervention (in-home AEDs) instead of providing fewer people with a more effective and more costly intervention (ICDs).Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74790/1/j.1524-4733.2006.00118.x.pd