Journal of clinical and translational research最新文献

Systems based on artificial intelligence and machine learning that facilitate decision making in health care are promising new tools in the era of 'personalized' or 'precision' medicine. As the volume of patient data and scientific evidence grows, these computerised decision support systems (DSS) have great potential to help healthcare professionals improve diagnosis and care for individual patients. However, the implementation of these tools in clinical care raises some foreseeable legal challenges for healthcare providers and DSS-suppliers in Europe: How does the use of complex and novel DSS relate to professional standards to provide a reasonable standard of care? What should be done in terms of testing before DSS can be used in regular practice? What are the potential liabilities of health care providers and DSS companies if a DSS fails to function well? How do legal requirements for the protection of patient data and general privacy rights apply to likely DSS scenarios? In this article, we provide an overview of the current law and its general implications for the use of DSS, from a European perspective. We conclude that healthcare providers and DSS-suppliers will have the best chance of meeting legal challenges if: they are first tested in translational research with the patients' explicit, informed consent; DSS-suppliers and healthcare providers are able to clarify and agree on their individual legal responsibilities, and; patients are properly informed about privacy risks and able to decide themselves whether their data can be used for other purposes, or are stored and processed outside the EU. DSS developers and healthcare providers will need to work together closely to ensure compliance with national and European regulations and standards required for reasonable and safe patient care.

Relevance for patients: Advanced digital decision support systems have the potential to improve patient diagnosis and care. In this article we discuss key legal issues to support translational research using DSS and ensure that they meet the high standards for protection of patient safety and privacy in Europe.

Being able to interpret 'null effects?is important for cumulative knowledge generation in science. To draw informative conclusions from null-effects, researchers need to move beyond the incorrect interpretation of a non-significant result in a null-hypothesis significance test as evidence of the absence of an effect. We explain how to statistically evaluate null-results using equivalence tests, Bayesian estimation, and Bayes factors. A worked example demonstrates how to apply these statistical tools and interpret the results. Finally, we explain how no statistical approach can actually prove that the null-hypothesis is true, and briefly discuss the philosophical differences between statistical approaches to examine null-effects. The increasing availability of easy-to-use software and online tools to perform equivalence tests, Bayesian estimation, and calculate Bayes factors make it timely and feasible to complement or move beyond traditional null-hypothesis tests, and allow researchers to draw more informative conclusions about null-effects.

Relevance for patients: Conclusions based on clinical trial data often focus on demonstrating differences due to treatments, despite demonstrating the absence of differences is an equally important statistical question. Researchers commonly conclude the absence of an effect based on the incorrect use of traditional methods. By providing an accessible overview of different approaches to exploring null-results, we hope researchers improve their statistical inferences. This should lead to a more accurate interpretation of studies, and facilitate knowledge generation about proposed treatments.

Ullmann et al. recently published a pilot study in Translational Psychiatry in which they report failing to find a statistically significant reduction in either hair cortisol or hair cortisone levels in circumcised men as compared with genitally intact (noncircumcised) men. Based on such null findings, the authors purport to have "refuted the psycho-pathological long-term effects of circumcision" and that the lack of significant results, "add to the growing body of evidence in the literature that male circumcision is not likely psychologically traumatizing across the life-span." In addition, they claim that they have proven a "healthy functionality of the LHPA axis" in men subjected to circumcision during infancy or childhood. However, it is not possible to draw any such conclusions on the basis of a null finding, especially one derived from an underpowered study in which the trend in the data suggest, if anything, that an adequately powered study may have shown the opposite of what the authors claim.

Relevance for patients: When combined with other weaknesses in study design, measurement, and interpretation, it becomes apparent that the authors' conclusions are not supported by their data.

Background: The half-life and mean residence time (MRT) of infused recombinant factor VIII (FVIII) concentrate are associated with pre-infusion levels of von Willebrand factor (VWF) in severely affected hemophilia A patients. It is currently unknown if individual FVIII concentrate half-life and MRT can be extended by increasing endogenous VWF levels. Aim: Our aim was to evaluate the effect of a 1-deamino-8-D-arginine vasopressin (DDAVP)-induced rise in VWF concentration on the pharmacokinetics of infused FVIII in hemophilia A patients.

Methods: Four adult hemophilia A patients participated in this cross-over, placebo-controlled study. Each patient received either intravenous DDAVP or placebo, one hour prior to administration of 50 IU/kg plasma-derived immune-affinity purified FVIII concentrate.

Results: The combined administration of DDAVP and FVIII concentrate was well tolerated. The levels of VWF Antigen (Ag) doubled after DDAVP, whereas they remained stable after placebo infusion. This rise in VWF Ag resulted in a slight modification of the pharmacokinetic parameters of FVIII concentrate. The MRT of FVIII concentrate increased in all patients (mean from 17.6 h to 19.9 h, p < 0.001, 95% CI for MRT change: +4.7 to -0.3 h). However, in vivo recoveries tended to decrease following DDAVP administration.

Conclusions: Collectively, these data show that administration of DDAVP did not improve the pharmacokinetics of FVIII concentrate in a clinically significant manner.

Relevance for patients: Our results indicate that no clinical benefit is to be expected from the modification in FVIII pharmacokinetics resulting from DDAVP-administration prior to infusion of FVIII concentrate in hemophilia A patients.

Background and Aim: Animal venoms comprise a mix of bioactive molecules with high affinity for multiple targets in cells and tissues. Scorpion and spider venoms and purified peptides exhibit significant effects on cancer cells, encompassing four potential mechanisms: 1) induction of cell cycle arrest, growth inhibition, and apoptosis; 2) inhibition of angiogenesis; 3) inhibition of invasion and metastasis; and 4) blocking of specific transmembrane channels. Tumor biology is complex and entails many intertwined processes, as reflected in the putative hallmarks of cancer. This complexity, however, gives rise to numerous (potential) pharmacological intervention sites. Molecules that target multiple proteins or pathways, such as components of animal venoms, may therefore be effective anti-cancer agents. The objective of this review was to address the anti-cancer properties and in vitro mechanisms of scorpion and spider venoms and toxins, and highlight current obstacles in translating the preclinical research to a clinical setting. Relevance for patients: Cancer is a considerable global contributor to disease-related death. Despite some advances being made, therapy remains palliative rather than curative for the majority of cancer indications. Consequently, more effective therapies need to be devised for poorly responding cancer types to optimize clinical cancer management. Scorpion and spider venoms may occupy a role in the development of improved anti-cancer modalities.

Background and Aim: Nutritional approaches that ameliorate cellular senescence may have the potential to counteract the effects of chronic disease. This study will investigate the effect of the Healthycell dietary supplement on markers of inflammation, oxidative stress, and DNA damage. Methods: Thirty adults between the ages of 18 and 55 were enrolled and randomly assigned to one of the two study conditions (n = 15 Healthycell and n = 15 placebo). Subjects participated in a four-week intervention and were assessed at baseline, four weeks, and six weeks (after a two-week washout period). Results: Pro-inflammatory cytokine interleukin (IL)-1α (t = 2.033; mean difference = -3.97 pg/ml; SE = 2.0; 95% CI: -8.0, -0.3; Cohen's d = 0.77; p = 0.05) decreased, while soluble cytokine receptors sTNFR-I (t = 2.057; mean difference = 52.39 pg/mL; SE = 18.5; 95% CI: 5.2, 99.6; Cohen's d = 0.53; p = 0.03) and sTNFR-II (t = 1.739; mean difference = 208.71 pg/ml; SE = 72.0; 95% CI: 24.4, 393.0; Cohen's d = 0.61; p = 0.02) increased in the treatment group versus control. C-reactive protein also rose in the Healthycell group during the trial (t = 2.568; mean difference = 1.41 mg/dL; SE = 0.4; 95% CI: 0.3, 2.5; Cohen's d = 0.66; p < 0.01), without accompanying increases in IL-6 and TNF-α. Additionally, cortisol levels decreased in the Healthycell group (t = 0.575; mean difference = -0.31 ug/dL; SE=0.1; 95% CI: -0.6, -0.03; Cohen's d = 0.88; p = 0.03). When groups were split by age (< 35 years vs. ≥ 35 years), 8-hydroxydeoxyguanosine, a marker of DNA damage, decreased in the older Healthycell group compared to placebo (t = 1.782; mean difference = -7.09 ng/mL; SE = 3.0; 95% CI: -13.3, -0.9; Cohen's d = 0.63; p = 0.03). Significant changes were also found for sTNFR-I, sTNFR-II, and IL-5 in the older group. All results were obtained from t tests by post-hoc analysis. Conclusions: Our findings show an improved inflammatory profile and decreased DNA damage. Additionally, the efficacy of Healthycell was primarily in older adults, where the processes that cause or are associated with cell senescence are more predominant. Relevance for patients: Healthycell may help to counteract the inflammatory effects of aging that lead to both cell senescence and the multitude of age-related chronic diseases.

Background: Acetaminophen (APAP) hepatotoxicity is a major cause of acute liver failure in many countries. Mechanistic studies in mice and humans have implicated formation of a reactive metabolite, mitochondrial dysfunction and oxidant stress as critical events in the pathophysiology of APAP-induced liver cell death. It was recently suggested that ATP released from necrotic cells can directly cause cell death in mouse hepatocytes and in a hepatoma cell line (HepG2).

Aim: To assess if ATP can directly cause cell toxicity in hepatocytes and evaluate their relevance in the human system.

Methods: Primary mouse hepatocytes, human HepG2 cells, the metabolically competent human HepaRG cell line and freshly isolated primary human hepatocytes were exposed to 10-100 µM ATP or ATγPin the presence or absence of 5-10 mM APAP for 9-24 h.

Results: ATP or ATγP was unable to directly cause cell toxicity in all 4 types of hepatocytes. In addition, ATP did not enhance APAP-induced cell death observed in primary mouse or human hepatocytes, or in HepaRG cells as measured by LDH release and by propidium iodide staining in primary mouse hepatocytes. Furthermore, addition of ATP did not cause mitochondrial dysfunction or enhance APAP-induced mitochondrial dysfunction in primary murine hepatocytes, although ATP did cause cell death in murine RAW macrophages.

Conclusions: It is unlikely that ATP released from necrotic cells can significantly affect cell death in human or mouse liver during APAP hepatotoxicity.

Relevance for patients: Understanding the mechanisms of APAP-induced cell injury is critical for identifying novel therapeutic targets to prevent liver injury and acute liver failure in APAP overdose patients.

Laser-assisted vascular welding (LAVW) is an experimental technique being developed as an alternative to suture anastomosis. In comparison to mechanical anastomosis, LAVW is less traumatic, non-immunogenic, provides immediate water tight sealant, and possibly a faster and easier procedure for minimally invasive surgery. This review focuses on technical advances to improve welding strength and to reduce thermal damage in LAVW. In terms of welding strength, LAVW has evolved from the photothermally-induced microvascular anastomosis, requiring stay sutures to support welding strength, to sutureless anastomoses of medium-sized vessels, withstanding physiological and supraphysiological pressure. Further improvements in anastomotic strength could be achieved by the use of chromophore-containing albumin solder and the employment of (biocompatible) polymeric scaffolds. The anastomotic strength and the stability of welds achieved with such a modality, referred to as scaffold- and solder-enhanced LAVW (ssLAVW), are dependent on the intermolecular bonding of solder molecules (cohesive bonding) and the bonding between solder and tissue collagen (adhesive bonding). Presently, the challenges of ssLAVW include (1) obtaining an optimal balance between cohesive and adhesive bonding and (2) minimizing thermal damage. The modulation of thermodynamics during welding, the application of semi-solid solder, and the use of a scaffold that supports both cohesive and adhesive strength are essential to improve welding strength and to limit thermal damage.