The analysis of drugs in biological fluids by high pressure liquid chromatography

Summary available: p. ii-iv

Analysis of umbilical cord tissue as an indicator of in utero exposure to toxic adulterating substances

In utero drug exposure is a significant public health threat to the well-being and normal development of the neonate. Recently, testing of umbilical cord tissue (UCT) has been employed to measure illicit drug exposure, as drugs used by the mother during the third trimester may be retained in the UCT. Focus has also been given to potential adverse health effects among drug users, resulting from exposure to pharmacologically active adulterants and cutting agents in the street drug supply. The in utero effects of these substances have not been well studied in humans, nor has their presence been demonstrated as a means for assessing adverse health effects in the neonate. Here, we describe the application of a novel test method to analyze UCT for the presence of more than 20 common adulterating/cutting substances via LC/Q-TOF. In total, 300 de-identified UCT samples were analyzed–all had previously tested positive for cocaine or opiates. Generally, the positivity rates of individual compounds were similar between the Cocaine and Opiates Subgroups, apart from levamisole, xylazine, dipyrone (metabolites), and promethazine. Many of the adulterants used in the street drug supply do have legitimate medicinal/therapeutic uses, including several of the compounds most frequently detected in this study. Caffeine and lidocaine were the most frequently identified compounds both individually (>70% each) and in combination with each other. Alternatively, levamisole, an adulterant with no legitimate therapeutic use, was present in 12% of cases. Importantly, this data demonstrates that the detection of traditional drugs of abuse may serve as indicators of potential in utero exposure to toxic adulterating substances during gestation. While there is cause for concern with respect to any unintentional drug exposure, illicit drug use during pregnancy, including uncontrolled dosing, poly-adulterant consumption, and the interactions of these drug mixtures, produces a significant public health threat to the neonate which warrants further study

Responses of stomatal features and photosynthesis to porewater N enrichment and elevated atmospheric CO2 in Phragmites australis, the common reed

PREMISE Biological invasions increasingly threaten native biodiversity and ecosystem services. One notable example is the common reed, Phragmites australis, which aggressively invades North American salt marshes. Elevated atmospheric CO2 and nitrogen pollution enhance its growth and facilitate invasion because P. australis responds more strongly to these enrichments than do native species. We investigated how modifications to stomatal features contribute to strong photosynthetic responses to CO2 and nitrogen enrichment in P. australis by evaluating stomatal shifts under experimental conditions and relating them to maximal stomatal conductance (g(wmax)) and photosynthetic rates.METHODS Plants were grown in situ in open-top chambers under ambient and elevated atmospheric CO2 (eCO(2)) and porewater nitrogen (N-enr) in a Chesapeake Bay tidal marsh. We measured light-saturated carbon assimilation rates (A(sat)) and stomatal characteristics, from which we calculated g(wmax) and determined whether CO2 and N-enr altered the relationship between g(wmax) and A(sat).RESULTS eCO(2) and N-enr enhanced both g(wmax) and A(sat), but to differing degrees; g(wmax) was more strongly influenced by N-enr through increases in stomatal density while A(sat) was more strongly stimulated by eCO(2). There was a positive relationship between g(wmax) and A(sat) that was not modified by eCO(2) or N-enr, individually or in combination.CONCLUSIONS Changes in stomatal features co-occur with previously described responses of P. australis to eCO(2) and N-enr. Complementary responses of stomatal length and density to these global change factors may facilitate greater stomatal conductance and carbon gain, contributing to the invasiveness of the introduced lineage

The Z-Wave Routing Protocol and Its Security Implications

Z-Wave is a proprietary technology used to integrate sensors and actuators over RF and perform smart home and office automation services. Lacking implementation details, consumers are under-informed on the security aptitude of their installed distributed sensing and actuating systems. While the Physical (PHY) and Medium Access Control (MAC) layers of the protocol have been made public, details regarding the network layer are not available for analysis. Using a real-world Z-Wave network, the frame forwarding and topology management aspects of the Z-Wave routing protocol are reverse engineered. A security analysis is also performed on the network under study to identify source and data integrity vulnerabilities of the routing protocol. It is discovered that the topology and routes may be modified by an outsider through the exploitation of the blind trust inherent to the routing nodes of the network. A Black Hole attack is conducted on a real-world Z-Wave network to demonstrate a well-known routing attack that exploits the exposed vulnerabilities. As a result of the discoveries, several recommendations are made to enhance the security of the routing protocol

Individualised pelvic floor muscle training in women with pelvic organ prolapse: a multicentre randomised controlled trial

<br>Background: Pelvic organ prolapse is common and is strongly associated with childbirth and increasing age. Women with prolapsed are often advised to do pelvic floor muscle exercises, but supporting evidence is limited. Our aim was to establish if one-to-one individualised pelvic floor muscle training (PFMT) is effective in reducing prolapse symptoms.</br> <br>Methods: A parallel‐group multicentre randomised controlled trial (ISRCTN35911035) in female outpatients with newly-diagnosed, symptomatic stage I, II or III prolapse, comparing five PFMT appointments over 16 weeks (n=225) versus a lifestyle advice leaflet (n=222). Treatment allocation was by remote computer allocation using minimisation. Our primary endpoint was participants’ self-report of prolapsed symptoms at 12 months. Group assignment was masked from outcome assessors. We compared outcomes between trial groups in an intention-to-treat analysis. The cost of PFMT and savings on subsequent treatments were calculated to estimate cost-effectiveness.</br> <br>Findings: Compared to the control group, the intervention group reported fewer prolapse symptoms at 12 months (mean difference between groups in change score 1.52, 95% CI [0.46, 2.59], p=0.0053); reported their prolapse to be “better” more often (57.2% versus 44.7%, difference 12.6%, 95% CI [1.1%, 24.1%], p=0.0336); and had an increased but non-significant odds of having less severe stage of prolapse at their 6-month clinical examination, (OR 1.47, 95% CI [0.97, 2.27], p=0.07). The control group had a greater uptake of other prolapse treatment (49.6% versus 24.1%, difference 25.5%, 95% CI [14.5%, 36.0%], p <0.0001). Findings were robust to missing data. The net cost of the 25 intervention was £131.61 per woman and the cost per one-point reduction in the symptom score was £86.59, 95% CI [£50.81, £286.11]. </br&gt

A Forward-Thinking Approach to Addressing the New Synthetic Opioid 2-Benzylbenzimidazole Nitazene Analogs by Liquid Chromatography-Tandem Quadrupole Mass Spectrometry (LC-QQQ-MS)

Novel psychoactive substances (NPS) continue to represent a threat to public health and safety. The number of new drugs in the latest emergent synthetic opioid class-the 2-benzylbenzimidazole analogs-also called the nitazenes-has begun to dominate the current new synthetic opioid (NSO) subclass of NPS. We describe a liquid chromatography-tandem quadrupole mass spectrometry method for the quantification of nine analogs and/or metabolites of drugs in this series: isotonitazene, metonitazene, protonitazene, etonitazene, clonitazene, flunitazene, N-desethyl isotonitazene, 5-amino isotonitazene and 4\u27-hydroxy nitazene in human whole blood, urine, and tissue. Samples were prepared for analysis using a basic liquid-liquid extraction. Chromatographic separation was achieved using a C-18 analytical column. Multiple reaction monitoring mode was used for detection. The calibration range for the analytes was 0.5-50 ng/mL (except for 5-amino isotonitazene, which was 1.0-50 ng/mL). The limit of detection was 0.1 ng/mL, and the limit of quantitation was 0.5 ng/mL. The method had no carryover or interferences. Ionization enhancement was observed but did not affect quantitation. All analytes passed the method validation assessment. Authentic human samples suspected of containing NSOs were obtained from a medical examiner and coroner offices, as well as partnering forensic toxicology laboratories. Isotonitazene was confirmed in 92 blood samples, and its metabolites were confirmed across various matrices. Metonitazene (n = 35), flunitazene (n = 5), protonitazene (n = 3), etodesnitazene (n = 2) and butonitazene (n = 1) were also detected in cases. These newly emerging 2-benzylbenzimidazole analogs were commonly found in combination with NPS benzodiazepines and opioids (e.g., flualprazolam, fentanyl). Nitazene analogs are potent esoteric drugs that may not be identified during routine toxicological screening, and specialized assays based on sensitive instrumentation are needed to accurately characterize these NSOs