Adverse Drug Reactions in a Complementary Medicine Hospital: A Prospective, Intensified Surveillance Study

Background. Anthroposophic medicine is one of the widely used approaches of complementary and alternative medicine. However, few prospective studies have generated safety data on its use. Objectives. We aimed to assess adverse drug reactions (ADRs) caused by anthroposophical medicines (AMEDs) in the anthroposophical Community Hospital Havelhoehe, GERMANY. Study Design and Methods. Between May and November 2007, patients of six medical wards were prospectively assessed for ADRs. Suspected ADRs occurring during hospitalization were documented and classified in terms of organ manifestation (WHO SOC-code), causality (according to the Uppsala Monitoring Centre WHO criteria), and severity. Only those ADRs with a severity of grade 2 and higher according to the CTCAE classification system are described here. Results. Of the 3,813 patients hospitalized, 174 patients (4.6%) experienced 211 ADRs (CTCAE grade 2/3 n = 191, 90.5%, CTCAE grade 4/5 n = 20, 9.5%) of which 57 ADRs (27.0%) were serious. The median age of patients with ADRs (62.1% females) was 72.0 (IQR: 61.0; 80.0). Six patients (0.2%) experienced six ADRs (2.8% of ADRs) caused by eight suspected AMEDs, all of which were mild reactions (grade 2). Conclusion. Our data show that ADRs caused by AMEDs occur rarely and are limited to mild symptoms

Translation-invariance of two-dimensional Gibbsian point processes

The conservation of translation as a symmetry in two-dimensional systems with interaction is a classical subject of statistical mechanics. Here we establish such a result for Gibbsian particle systems with two-body interaction, where the interesting cases of singular, hard-core and discontinuous interaction are included. We start with the special case of pure hard core repulsion in order to show how to treat hard cores in general.Comment: 44 pages, 6 figure

Conditional Intensity and Gibbsianness of Determinantal Point Processes

The Papangelou intensities of determinantal (or fermion) point processes are investigated. These exhibit a monotonicity property expressing the repulsive nature of the interaction, and satisfy a bound implying stochastic domination by a Poisson point process. We also show that determinantal point processes satisfy the so-called condition $(\Sigma_{\lambda})$ which is a general form of Gibbsianness. Under a continuity assumption, the Gibbsian conditional probabilities can be identified explicitly.Comment: revised and extende

Enteral lactoferrin supplementation for very preterm infants: a randomised placebo-controlled trial

Background Infections acquired in hospital are an important cause of morbidity and mortality in very preterm infants. Several small trials have suggested that supplementing the enteral diet of very preterm infants with lactoferrin, an antimicrobial protein processed from cow's milk, prevents infections and associated complications. The aim of this large randomised controlled trial was to collect data to enhance the validity and applicability of the evidence from previous trials to inform practice. Methods In this randomised placebo-controlled trial, we recruited very preterm infants born before 32 weeks' gestation in 37 UK hospitals and younger than 72 h at randomisation. Exclusion criteria were presence of a severe congenital anomaly, anticipated enteral fasting for longer than 14 days, or no realistic prospect of survival. Eligible infants were randomly assigned (1:1) to receive either enteral bovine lactoferrin (150 mg/kg per day; maximum 300 mg/day; lactoferrin group) or sucrose (same dose; control group) once daily until 34 weeks' postmenstrual age. Web-based randomisation minimised for recruitment site, gestation (completed weeks), sex, and single versus multifetal pregnancy. Parents, caregivers, and outcome assessors were unaware of group assignment. The primary outcome was microbiologically confirmed or clinically suspected late-onset infection (occurring >72 h after birth), which was assessed in all participants for whom primary outcome data was available by calculating the relative risk ratio with 95% CI between the two groups. The trial is registered with the International Standard Randomised Controlled Trial Number 88261002. Findings We recruited 2203 participants between May 7, 2014, and Sept 28, 2017, of whom 1099 were assigned to the lactoferrin group and 1104 to the control group. Four infants had consent withdrawn or unconfirmed, leaving 1098 infants in the lactoferrin group and 1101 in the sucrose group. Primary outcome data for 2182 infants (1093 [99·5%] of 1098 in the lactoferrin group and 1089 [99·0] of 1101 in the control group) were available for inclusion in the modified intention-to-treat analyses. 316 (29%) of 1093 infants in the intervention group acquired a late-onset infection versus 334 (31%) of 1089 in the control group. The risk ratio adjusted for minimisation factors was 0·95 (95% CI 0·86–1·04; p=0·233). During the trial there were 16 serious adverse events for infants in the lactoferrin group and 10 for infants in the control group. Two events in the lactoferrin group (one case of blood in stool and one death after intestinal perforation) were assessed as being possibly related to the trial intervention. Interpretation Enteral supplementation with bovine lactoferrin does not reduce the risk of late-onset infection in very preterm infants. These data do not support its routine use to prevent late-onset infection and associated morbidity or mortality in very preterm infants. Funding UK National Institute for Health Research Health Technology Assessment programme (10/57/49)

Inhibition of the MID1 protein complex: a novel approach targeting APP protein synthesis

Alzheimer's disease (AD) is characterized by two neuropathological hallmarks: senile plaques, which are composed of amyloid-β (Aβ) peptides, and neurofibrillary tangles, which are composed of hyperphosphorylated tau protein. Aβ peptides are derived from sequential proteolytic cleavage of the amyloid precursor protein (APP). In this study, we identified a so far unknown mode of regulation of APP protein synthesis involving the MID1 protein complex: MID1 binds to and regulates the translation of APP mRNA. The underlying mode of action of MID1 involves the mTOR pathway. Thus, inhibition of the MID1 complex reduces the APP protein level in cultures of primary neurons. Based on this, we used one compound that we discovered previously to interfere with the MID1 complex, metformin, for in vivo experiments. Indeed, long-term treatment with metformin decreased APP protein expression levels and consequently Aβ in an AD mouse model. Importantly, we have initiated the metformin treatment late in life, at a time-point where mice were in an already progressed state of the disease, and could observe an improved behavioral phenotype. These findings together with our previous observation, showing that inhibition of the MID1 complex by metformin also decreases tau phosphorylation, make the MID1 complex a particularly interesting drug target for treating AD

Enteral lactoferrin supplementation for very preterm infants: a randomised placebo-controlled trial

Background Infections acquired in hospital are an important cause of morbidity and mortality in very preterm infants. Several small trials have suggested that supplementing the enteral diet of very preterm infants with lactoferrin, an antimicrobial protein processed from cow's milk, prevents infections and associated complications. The aim of this large randomised controlled trial was to collect data to enhance the validity and applicability of the evidence from previous trials to inform practice. Methods In this randomised placebo-controlled trial, we recruited very preterm infants born before 32 weeks' gestation in 37 UK hospitals and younger than 72 h at randomisation. Exclusion criteria were presence of a severe congenital anomaly, anticipated enteral fasting for longer than 14 days, or no realistic prospect of survival. Eligible infants were randomly assigned (1:1) to receive either enteral bovine lactoferrin (150 mg/kg per day; maximum 300 mg/day; lactoferrin group) or sucrose (same dose; control group) once daily until 34 weeks' postmenstrual age. Web-based randomisation minimised for recruitment site, gestation (completed weeks), sex, and single versus multifetal pregnancy. Parents, caregivers, and outcome assessors were unaware of group assignment. The primary outcome was microbiologically confirmed or clinically suspected late-onset infection (occurring >72 h after birth), which was assessed in all participants for whom primary outcome data was available by calculating the relative risk ratio with 95% CI between the two groups. The trial is registered with the International Standard Randomised Controlled Trial Number 88261002. Findings We recruited 2203 participants between May 7, 2014, and Sept 28, 2017, of whom 1099 were assigned to the lactoferrin group and 1104 to the control group. Four infants had consent withdrawn or unconfirmed, leaving 1098 infants in the lactoferrin group and 1101 in the sucrose group. Primary outcome data for 2182 infants (1093 [99·5%] of 1098 in the lactoferrin group and 1089 [99·0] of 1101 in the control group) were available for inclusion in the modified intention-to-treat analyses. 316 (29%) of 1093 infants in the intervention group acquired a late-onset infection versus 334 (31%) of 1089 in the control group. The risk ratio adjusted for minimisation factors was 0·95 (95% CI 0·86–1·04; p=0·233). During the trial there were 16 serious adverse events for infants in the lactoferrin group and 10 for infants in the control group. Two events in the lactoferrin group (one case of blood in stool and one death after intestinal perforation) were assessed as being possibly related to the trial intervention. Interpretation Enteral supplementation with bovine lactoferrin does not reduce the risk of late-onset infection in very preterm infants. These data do not support its routine use to prevent late-onset infection and associated morbidity or mortality in very preterm infants. Funding UK National Institute for Health Research Health Technology Assessment programme (10/57/49)

Educational intervention to improve physician reporting of adverse drug reactions (ADRs) in a primary care setting in complementary and alternative medicine

<p>Abstract</p> <p>Background</p> <p>Recent studies have shown that adverse drug reactions (ADRs) are underreported. This may be particularly true of ADRs associated with complementary and alternative medicine (CAM). Data on CAM-related ADRs, however, are sparse.</p> <p>Objective was to evaluate the impact of an educational intervention and monitoring programme designed to improve physician reporting of ADRs in a primary care setting.</p> <p>Methods</p> <p>A prospective multicentre study with 38 primary care practitioners specialized in CAM was conducted from January 2004 through June 2007. After 21 month all physicians received an educational intervention in terms of face-to-face training to assist them in classifying and reporting ADRs. The study centre monitored the quantity and quality of ADR reports and analysed the results.</p> <p>To measure changes in the ADR reporting rate, the median number of ADR reports and interquartile range (IQR) were calculated before and after the educational intervention. The pre-intervention and post-intervention quality of the reports was assessed in terms of changes in the completeness of data provided for obligatory items. Interrater reliability between the physicians and the study centre was calculated using Cohen's kappa with a 95% confidence interval (CI). We used Mann Whitney U-test for testing continuous data and chi-square test was used for categorical data. The level of statistical significance was set at <it>P </it>< 0.05.</p> <p>Results</p> <p>A total of 404 ADRs were reported during the complete study period. An initial 148% increase (<it>P </it>= 0.001) in the number of ADR reports was observed after the educational intervention. Compared to baseline the postinterventional number of ADR reportings was statistically significant higher (P < 0.005) through the first 16 months after the intervention but not significant in the last 4-month period (median: 8.00 (IQR [2.75; 8.75]; P = 0.605). The completeness of the ADR reports increased from 80.3% before to 90.7% after the intervention. The completeness of the item for classifying ADRs as serious or non-serious increased significantly (<it>P </it>< 0.001) after the educational intervention. The quality of ADR reports increased from kappa 0.15 (95% CI: 0.08; 0.29) before to 0.43 (95% CI: 0.23; 0.63) after the intervention.</p> <p>Conclusion</p> <p>The results of the present study demonstrate that an educational intervention can increase physician awareness of ADRs. Participating physicians were able to incorporate the knowledge they had gained from face-to-face training into their daily clinical practice. However, the effects of the intervention were temporary.</p

Basic kinetic wealth-exchange models: common features and open problems

We review the basic kinetic wealth-exchange models of Angle [J. Angle, Social Forces 65 (1986) 293; J. Math. Sociol. 26 (2002) 217], Bennati [E. Bennati, Rivista Internazionale di Scienze Economiche e Commerciali 35 (1988) 735], Chakraborti and Chakrabarti [A. Chakraborti, B. K. Chakrabarti, Eur. Phys. J. B 17 (2000) 167], and of Dragulescu and Yakovenko [A. Dragulescu, V. M. Yakovenko, Eur. Phys. J. B 17 (2000) 723]. Analytical fitting forms for the equilibrium wealth distributions are proposed. The influence of heterogeneity is investigated, the appearance of the fat tail in the wealth distribution and the relaxation to equilibrium are discussed. A unified reformulation of the models considered is suggested.Comment: Updated version; 9 pages, 5 figures, 2 table