The Regulatory Challenges of Placing Dietary Ingredients on the European and US Market.

The DSHEA is 30 years old and its place in providing legitimate protections for public health through relevant agency oversight has created a patchwork of legal and scientific requirements. In contrast, the European Union has rules on supplements and permitted ingredients. Given the context of a global supply chain for food ingredients any conflict between the legality of ingredients between the U.S/EU can inhibit the economic viability of international trade. The purpose of this review is to contrast these different systems of legislative oversight. The analysis of both markets demonstrates a fragmentation in what are considered legal food ingredients between country wide harmonization and state rules and related interpretation. There are many commonalities in this regard between the U.S/EU, from borderline medicinal classifications to their resultant preclusion from food use. However, the codified legal system existing within the EU and excessive guidance can be viewed as time consuming and inflexible, especially for placing new ingredients on the market. The US in contrast is in a holding pattern for legislative interpretation regarding NDIs, GRAS and possible drug preclusion laws. As we hit the anniversary of the DSHEA recent commentary from U.S./EU central authorities point to increased international co-operation in ingredient safety assessments but whether this results in friction-free access between markets is to be determined.

Estimations of the effective Young's modulus of specimens prepared by fused filament fabrication.

The elastic response of homogeneous isotropic materials is most commonly represented by their Young's modulus (E), but geometric variability associated with additive manufacturing results in materials that are neither homogeneous nor isotropic. Here we investigated methods to estimate the effective elastic modulus (Eeff) of samples fabricated by fused filament fabrication. We conducted finite element analysis (FEA) on printed samples based on material properties and CT-scanned geometries. The analysis revealed how the layer structure of a specimen altered the internal stress distribution and the resulting Eeff. We also investigated different empirical methods to estimate Eeff as guides. We envision the findings from our study can provide guidelines for modulus estimation of as-printed specimens, with the potential of applying to other extrusion-based additive manufacturing technologies.

Temporary faecal diversion in ileocolic resection for Crohn's disease: is there an impact on long-term surgical recurrence?

AIM: Temporary faecal diversion after ileocolic resection (ICR) for Crohn's disease reduces postoperative anastomotic complications in high-risk patients. The aim of this study was to assess if this approach also reduces long-term surgical recurrence. METHOD: This was a multicentre retrospective review of prospectively maintained databases. Patient demographics, medical and surgical details were collected by three specialist centres. All patients had undergone an ICR between 2000 and 2012. The primary end-point was surgical recurrence. RESULTS: Three hundred and twelve patients (80%) underwent an ICR without covering ileostomy (one stage). Seventy-seven (20%) had undergone an ICR with end ileostomy/double-barrel ileostomy/enterocolostomy followed by closure (two stage). The median follow-up was 105 months [interquartile range (IQR) 76-136 months]. The median time to ileostomy closure was 9 months (IQR 5-12 months). There was no significant difference in surgical recurrence between the one- and two-stage groups (18% vs 16%, P = 0.94). We noted that smokers (20% vs 34%, P = 0.01) and patients with penetrating disease (28% vs 52%, P < 0.01) were more likely to be defunctioned. A reduced recurrence rate was observed in the small high-risk group of patients who were smokers with penetrating disease behaviour treated with a two-stage strategy (0/10 vs 4/7, P = 0.12). CONCLUSION: Despite having higher baseline risk factors, the results in terms of rate of surgical recurrence over 9 years are similar for patients having a two-stage compared with a one-stage procedure.

AMB2018-03: Benchmark Physical Property Measurements for Material Extrusion Additive Manufacturing of Polycarbonate.

Material extrusion (MatEx) is finding increasing applications in additive manufacturing of thermoplastics due to the ease of use and the ability to process disparate polymers. Since part strength is anisotropic and frequently deviates negatively with respect to parts produced by injection molding, an urgent challenge is to predict final properties of parts made through this method. A nascent effort is underway to develop theoretical and computational models of MatEx part properties, but these efforts require comprehensive experimental data for guidance and validation. As part of the AM-Bench framework, we provide here a thorough set of measurements on a model system: polycarbonate printed in a simple rectangular shape. For the precursor material (as-received filament), we perform rheology, gel permeation chromatography, and dynamical mechanical analysis, to ascertain critical material parameters such as molar mass distribution, glass transition, and shear thinning. Following processing, we conduct X-ray computed tomography, scanning electron microscopy, depth sensing indentation, and atomic force microscopy modulus mapping. These measurements provide information related to pores, method of failure, and local modulus variations. Finally, we conduct tensile testing to assess strength and degree of anisotropy of mechanical properties. We find several effects that lead to degradation of tensile properties including the presence of pore networks, poor interfacial bonding, variations in interfacial mechanical behavior between rasters, and variable interaction of the neighboring builds within the melt state. The results provide insight into the processing-structure-property relationships and should serve as benchmarks for the development of mechanical models.

Randomized clinical trial comparing collagen plug and advancement flap for trans-sphincteric anal fistula.

BACKGROUND: The role of a collagen plug for treating anal fistula is not well established. A randomized prospective multicentre non-inferiority study of surgical treatment of trans-sphincteric cryptogenic fistulas was undertaken, comparing the anal fistula plug with the mucosal advancement flap with regard to fistula recurrence rate and functional outcome. METHODS: Patients with an anal fistula were evaluated for eligibility in three centres, and randomized to either mucosal advancement flap surgery or collagen plug, with clinical follow-up at 3 and 12 months. The primary outcome was the fistula recurrence rate. Anal pain (visual analogue scale), anal incontinence (St Mark's score) and quality of life (Short Form 36 questionnaire) were also reported. RESULTS: Ninety-four patients were included; 48 were allocated to the plug procedure and 46 to advancement flap surgery. The median follow-up was 12 (range 9-24) months. The recurrence rate at 12 months was 66 per cent (27 of 41 patients) in the plug group and 38 per cent (15 of 40) in the flap group (P = 0·006). Anal pain was reduced after operation in both groups. Anal incontinence did not change in the follow-up period. Patients reported an increased quality of life after 3 months. There were no differences between the groups with regard to pain, incontinence or quality of life. CONCLUSION: There was a considerably higher recurrence rate after the anal fistula plug procedure than following advancement flap repair. Registration number: NCT01021774 (http://www.clinicaltrials.gov).

The Safety, Pharmacokinetics, and Nervous System Effects of Two Natural Sources of Caffeine in Healthy Adult Males.

This double-blind crossover clinical trial randomized 12 adult males to receive 200 mg of caffeine from a green coffee extract, a guayusa leaf extract, and a synthetic control to compare their safety, absorption, and effect on neurotransmitters. The results showed no statistically significant changes in blood pressure or heart rate from baseline to 120 min postdose of each natural source compared with changes from baseline in the control (0.094 < = P < = 0.910). The ratios of Cmax , AUC0-4 , and AUC0-∞ of each natural source to the control were bioequivalent by US Food and Drug Administration standards (90% CI within 80-125%). The guayusa leaf extract stimulated a significantly lower increase in epinephrine compared with the control (+0.5 vs. +2.78 µg/gCr, P = 0.04), while the green coffee extract provoked an increase in epinephrine similar to the control (+3.21 vs. +2.78 µg/gCr, P = 0.569). Implications for future clinical research are discussed.

Infrared thermography of welding zones produced by polymer extrusion additive manufacturing.

In common thermoplastic additive manufacturing (AM) processes, a solid polymer filament is melted, extruded though a rastering nozzle, welded onto neighboring layers and solidified. The temperature of the polymer at each of these stages is the key parameter governing these non-equilibrium processes, but due to its strong spatial and temporal variations, it is difficult to measure accurately. Here we utilize infrared (IR) imaging - in conjunction with necessary reflection corrections and calibration procedures - to measure these temperature profiles of a model polymer during 3D printing. From the temperature profiles of the printed layer (road) and sublayers, the temporal profile of the crucially important weld temperatures can be obtained. Under typical printing conditions, the weld temperature decreases at a rate of approximately 100 °C/s and remains above the glass transition temperature for approximately 1 s. These measurement methods are a first step in the development of strategies to control and model the printing processes and in the ability to develop models that correlate critical part strength with material and processing parameters.

STANDARD REFERENCE MATERIALS FOR THE POLYMERS INDUSTRY.

The National Institute of Standards and Technology (NIST) provides science, industry, and government with a central source of well-characterized materials certified for chemical composition or for some chemical or physical property. These materials are designated Standard Reference Materials® (SRMs) and are used to calibrate measuring instruments, to evaluate methods and systems, or to produce scientific data that can be referred readily to a common base. In this paper, we discuss the history of polymer based SRMs, their current status, and challenges and opportunities to develop new standards to address industrial measurement challenges.

Cost-effective expression and purification of antimicrobial and host defense peptides in Escherichia coli.

Cationic antimicrobial host defense peptides (HDPs) combat infection by directly killing a wide variety of microbes, and/or modulating host immunity. HDPs have great therapeutic potential against antibiotic-resistant bacteria, viruses and even parasites, but there are substantial roadblocks to their therapeutic application. High manufacturing costs associated with amino acid precursors have limited the delivery of inexpensive therapeutics through industrial-scale chemical synthesis. Conversely, the production of peptides in bacteria by recombinant DNA technology has been impeded by the antimicrobial activity of these peptides and their susceptibility to proteolytic degradation, while subsequent purification of recombinant peptides often requires multiple steps and has not been cost-effective. Here we have developed methodologies appropriate for large-scale industrial production of HDPs; in particular, we describe (i) a method, using fusions to SUMO, for producing high yields of intact recombinant HDPs in bacteria without significant toxicity and (ii) a simplified 2-step purification method appropriate for industrial use. We have used this method to produce seven HDPs to date (IDR1, MX226, LL37, CRAMP, HHC-10, E5 and E6). Using this technology, pilot-scale fermentation (10L) was performed to produce large quantities of biologically active cationic peptides. Together, these data indicate that this new method represents a cost-effective means to enable commercial enterprises to produce HDPs in large-scale under Good Laboratory Manufacturing Practice (GMP) conditions for therapeutic application in humans.

Pregnancy outcomes, infant mortality, and arsenic in drinking water in West Bengal, India.

Between 2001 and 2003, the authors studied pregnancy outcomes and infant mortality among 202 married women in West Bengal, India. Reproductive histories were ascertained using structured interviews. Arsenic exposure during each pregnancy, including all water sources used, was assessed; this involved measurements from 409 wells. Odds ratios for spontaneous abortion, stillbirth, neonatal mortality, and infant mortality were estimated with logistic regression based on the method of generalized estimating equations. Exposure to high concentrations of arsenic (> or =200 microg/liter) during pregnancy was associated with a sixfold increased risk of stillbirth after adjustment for potential confounders (odds ratio (OR) = 6.07, 95% confidence interval (CI): 1.54, 24.0; p = 0.01). Arsenic-related skin lesions were found in 12 women who had a substantially increased risk of stillbirth (OR = 13.1, 95% CI: 3.17, 54.0; p = 0.002). The odds ratio for neonatal death was 2.81 (95% CI: 0.73, 10.8). No association was found between arsenic exposure and spontaneous abortion (OR = 1.01, 95% CI: 0.38, 2.70) or overall infant mortality (OR = 1.33, 95% CI: 0.43, 4.04). This study adds to the limited evidence that exposure to high concentrations of arsenic during pregnancy increases the risk of stillbirth. However, there was no indication of the increased rates of spontaneous abortion and overall infant mortality that have been reported in some studies.

A physiologically based toxicokinetic model of inhalation exposure to xylenes in Caucasian men.

Widespread exposure to the volatile aromatic hydrocarbons, ortho-, meta-, and para-xylene occurs in many industries including the manufacture of plastics, pharmaceuticals, and synthetic fibers. This paper describes the development of a physiologically based toxicokinetic model using biomonitoring data to quantify the kinetics of ortho-, meta-, and para-xylenes. Serial blood concentrations of deuterium-labeled xylene isomers were obtained over 4 days after 37 controlled, 2h inhalation exposures to different concentrations of the isomers. Peak toxicant concentrations in blood occurred in all subjects at the termination of exposure. Systemic clearance averaged 116 L/h+/-34 L/h, 117 L/h+/-23 L/h, and 129 L/h+/-33 L/h for ortho-, para-, and meta-xylene, respectively. The half-life of each toxicant in the terminal phase (>90 h post-exposure) was fit by the model, yielding values of 30.3+/-10.2 h for para-xylene, 33.0+/-11.7 h for meta-xylene and 38.5+/-18.2 h for ortho-xylene. Significant isomeric differences were found (p<0.05) for toxicant half-life, clearance and extrahepatic metabolism. Inter-individual variability seen in this study suggests that airborne concentration guidelines may not protect all workers. A Biological Exposure Index is preferred for this purpose since it is integrative and reflective of inter-individual kinetic variability.

Role of bovine herpesvirus 4 in bacterial bovine mastitis.

In order to study the role played by bovine herpesvirus 4 (BoHV-4) in bovine mastitis, PCR experiments were performed on a Hungarian dairy herd of 2000 cows. Milk cells were tested with a nested PCR adjusted to detect the virus in the milk. Thirty to forty-one percentage of the udders of 101 cows with bacterial mastitis (Escherichia coli, Streptococcus uberis or Staphylococcus aureus) gave positive results, whereas less than 6% of the milk samples were positive for BoHV-4 from 118 animals with healthy udders. The mastitis status of these 118 healthy cows was followed throughout the milking period; 4.2% had clinical, and 25.42% had subclinical mastitis. By the end of the milking period, more than 90% of the cows shed the virus in their milk, regardless of the bacterial status of the udder. No correlation was found between the virus shed, the somatic cell count, and the bacterial status of the udder. Viral DNA was detected in the wall of the milk duct. These results demonstrate that BoHV-4 neither causes mastitis directly nor plays a role in the initiation of the process, but later, when bacterial infection of the udder occurs, the reactivated virus replicates in the immune cells of the udder and/or in the epithelial cells of the milk ducts and may be responsible for more severe, prolonged mastitis. As mastitis is a crucial problem of milk production, this virus may be considered a possible predisposing factor and also an agent of secondary udder infections in prolonged mastitis cases.

Anaplasma phagocytophilum: an emerging tick-borne pathogen in Hungary and Central Eastern Europe.

Anaplasma phagocytophilum (formerly Ehrlichia phagocytophila, Ehrlichia equi and Anaplasma phagocytophila) is the causative agent of granulocytic ehrlichiosis (anaplasmosis) in humans, horses, sheep, cattle, dogs and cats. In the present study, 452 European sheep ticks (Ixodes ricinus) collected from 100 red foxes (Vulpes vulpes) in Hungary were tested for the pathogen, as 112 pools each containing five or fewer ticks from one fox. Six of the pools, representing ticks from six different foxes, were found infected in the PCR-based test employed. This is the first time that A. phagocytophilum has been reported in Hungary. A summary of the information available from Central Eastern Europe on the prevalence of A. phagocytophilum in ticks, its seroprevalence in humans, and the number of human cases of granulocytic ehrlichiosis known in the region is presented.

Assessment of PCB congener analytical methods: do they meet risk assessment needs?

Congener-specific PCB analysis allows use of toxic equivalency (TEQ) TCDD-based risk assessment approaches when analytical methods are sufficiently sensitive. Many efforts to analyze fish samples for PCB congeners report the majority of samples as non-detects; these data are of little use for human health risk assessment if the limits of analytical detection exceed levels of potential health concern. However, increasing analytical sensitivity is costly and technically difficult. An approach to assess analytical sensitivity needs for risk assessment by defining toxicological endpoints of concern and acceptable risk levels is presented. This framework was applied to assessment of potential PCB TEQ cancer risks to the general United States population and tribal consumers of Columbia River fish, but may be easily adjusted for other situations. A probabilistic model was used to calculate the necessary analytical sensitivity for PCB TEQ cancer risk assessment using the Environmental Protection Agency's new draft cancer risk slope factor for TCDD and fish consumption data. Desired levels of analytical sensitivity were estimated for the congener expected to contribute the most to PCB TEQ, PCB 126, and compared to limits of detection for various analytical methods. The financial and health value of methods with different levels of analytical sensitivity were compared using a value of information approach, which includes analytical cost and cost of potential health outcomes, and a proposed risk assessment utility approach which considers the relative health protectiveness of analytical options non-monetarily. Sensitivity analyses indicate that average consumption rate, cancer risk slope factor choice, and knowledge of existing PCB contamination are important considerations for planning PCB congener analysis.

An acute clinical trial evaluating the cardiovascular effects of an herbal ephedra-caffeine weight loss product in healthy overweight adults.

OBJECTIVE: This study was undertaken to determine the acute effects of a commercial weight loss supplement containing herbal ephedrine and caffeine on cardiovascular function in healthy overweight adults. DESIGN: Randomized double blind clinical trial evaluating the cardiovascular effects of an ephedra-caffeine (Xenadrine(TM); XEN) based herbal product vs placebo (PLA). SUBJECTS: Twenty-seven healthy overweight adults (age 21-60 y; body mass index > or = 25 kg/m(2)). MEASUREMENTS: Systolic and diastolic blood pressure, heart rate, serial electrocardiograms (EKG) and Doppler echocardiograms. RESULTS: A comparison of means between the groups indicated no statistically significant differences at the start of the study for the variables above. There were no serious adverse events. When examining the effects of XEN vs PLA on cardiovascular health/function, there were no significant effects observed in heart rate, systolic blood pressure, diastolic blood pressure, left ventricular ejection fraction, heart valve function or in cardiovascular physiology within the parameters measured. CONCLUSION: These findings indicate that, over a 14-day period, ingestion of the commercial weight loss supplement in a healthy overweight population did not produce any noticeable cardiovascular side effects.

The metabolism of orally ingested 19-nor-4-androstene-3,17-dione and 19-nor-4-androstene-3,17-diol in healthy, resistance-trained men.

The purpose of this investigation was to determine the metabolism of 2 over-the-counter steroids (Nortesten, which contains 36 mg of 19-nor-4-androstene-3,17-dione and 36 mg of 19-nor-4-androstene-3,17-diol) in healthy, resistance-trained men. Subjects were administered either low (72 mg) or high doses (144 mg) of Nortesten twice daily for 10 days. All subjects tested positive via urinalysis for the presence of nortestosterone at days 3, 5, 7, and 10. There was no change in the urine testosterone-epitestosterone ratio at any day. Furthermore, as determined by serum chemistry tests, there was no effect on renal, hepatic, hematological, or bone marrow function. Thus, short-term ingestion of 19-nor-4-androstene-3,17-dione and 19-nor-4-androstene-3,17-diol may result in a positive drug test result without any harmful side effects.