Generating Relevant Information from Patients in the Technology-Enhanced Era of Patient-Focused Drug Development: Opportunities and Challenges.

The era of patient-focused drug development (PFDD) brings with it a greater use of patient-reported outcome measures (PROMs) in clinical trials. This is facilitated through electronic technology designed to capture PROM data. However, PFDD goes beyond just PROMs, and technology has a key role in capturing timely and patient-relevant information through active and passive means to inform study endpoints. This brief paper aims to highlight four trends the authors have observed across the pharmaceutical industry in using technology to enhance PFDD: (1) capturing qualitative data from patients; (2) using digital health technology tools (DHTTs); (3) employing reactive technology-enabled clinical outcome assessments TeCOA; and (4) generating passive patient experience data. Opportunities and challenges associated with these trends are discussed, and a 'call to action' is made to consolidate learning and understanding across science, medical and technology disciplines, and to conduct collaborative research to improve the opportunities and minimize the challenges.

A large source of cloud condensation nuclei from new particle formation in the tropics.

Cloud condensation nuclei (CCN) can affect cloud properties and therefore Earth's radiative balance1-3. New particle formation (NPF) from condensable vapours in the free troposphere has been suggested to contribute to CCN, especially in remote, pristine atmospheric regions4, but direct evidence is sparse, and the magnitude of this contribution is uncertain5-7. Here we use in situ aircraft measurements of vertical profiles of aerosol size distributions to present a global-scale survey of NPF occurrence. We observe intense NPF at high altitudes in tropical convective regions over both Pacific and Atlantic oceans. Together with the results of chemical-transport models, our findings indicate that NPF persists at all longitudes as a global-scale band in the tropical upper troposphere, covering about 40 per cent of Earth's surface. Furthermore, we find that this NPF in the tropical upper troposphere is a globally important source of CCN in the lower troposphere, where CCN can affect cloud properties. Our findings suggest that the production of CCN as new particles descend towards the surface is not adequately captured in global models, which tend to underestimate both the magnitude of tropical upper tropospheric NPF and the subsequent growth of new particles to CCN sizes.

Watching from a distance: A robotically controlled laser and real-time subject tracking software for the study of conditioned predator/prey-like interactions.

BACKGROUND: The physical distance between predator and prey is a primary determinant of behavior, yet few paradigms exist to study this reliably in rodents. NEW METHOD: The utility of a robotically controlled laser for use in a predator-prey-like (PPL) paradigm was explored for use in rats. This involved the construction of a robotic two-dimensional gimbal to dynamically position a laser beam in a behavioral test chamber. Custom software was used to control the trajectory and final laser position in response to user input on a console. The software also detected the location of the laser beam and the rodent continuously so that the dynamics of the distance between them could be analyzed. When the animal or laser beam came within a fixed distance the animal would either be rewarded with electrical brain stimulation or shocked subcutaneously. RESULTS: Animals that received rewarding electrical brain stimulation could learn to chase the laser beam, while animals that received aversive subcutaneous shock learned to actively avoid the laser beam in the PPL paradigm. Mathematical computations are presented which describe the dynamic interaction of the laser and rodent. COMPARISON WITH EXISTING METHODS: The robotic laser offers a neutral stimulus to train rodents in an open field and is the first device to be versatile enough to assess distance between predator and prey in real time. CONCLUSIONS: With ongoing behavioral testing this tool will permit the neurobiological investigation of predator/prey-like relationships in rodents, and may have future implications for prosthetic limb development through brain-machine interfaces.

Second-order conditioning of LiCl-induced gaping with flavor and contextual cues.

Conditioned gaping occurs through a classically conditioned association between a flavor or a context (CS) and an unconditioned stimulus (US) that produces nausea, such as lithium chloride (LiCl; US). Rats display conditioned gaping to a flavor or context previously associated with nausea; thus, our aim was to investigate whether rats acquire second-order conditioning to a flavor experienced in a nausea-paired context. In Experiment 1, rats were assigned to one of three groups, based upon the contingency of the first order pairing (CS1 context and LiCl) and the contingency of the second-order pairing (CS2 saccharin CS1 context) including: Group Paired/Paired (P/P), Group Paired/Unpaired (P/U) and Group Unpaired/Paired (U/P). In the initial context conditioning, rats were injected with LiCl (Paired) or Saline (Unpaired) prior to a 30 min confinement in a distinctive context (CS1). Drug-free second-order conditioning training among Groups P/P and U/P then consisted of a 5 min intraoral infusion of 0.1 % saccharin (CS2) in the context (CS1), while Group P/U received saccharin in the home cage 24 hr prior to the CS1 exposure. Twenty four hr later, the rats were tested for second-order conditioning during a 2 min taste reactivity (TR) test. Saccharin (CS2) elicited gaping in Group P/P, but not Groups P/U or U/P. Experiment 2 revealed that second-order conditioning was produced in rats given 4 or 8 first-order conditioning trials, but not 2 trials. These results demonstrate that an excitatory contextual CS+ has the potential to confer second-order conditioning to a novel flavor in the absence of any direct pairing with LiCl.

Illustrative assessment of human health issues arising from the potential release of chemotoxic substances from a generic geological disposal facility for radioactive waste.

Many countries have a programme for developing an underground geological disposal facility for radioactive waste. A case study is provided herein on the illustrative assessment of human health issues arising from the potential release of chemotoxic and radioactive substances from a generic geological disposal facility (GDF) for radioactive waste. The illustrative assessment uses a source-pathway-receptor methodology and considers a number of human exposure pathways. Estimated exposures are compared with authoritative toxicological assessment criteria. The possibility of additive and synergistic effects resulting from exposures to mixtures of chemical contaminants or a combination of radiotoxic and chemotoxic substances is considered. The case study provides an illustration of how to assess human health issues arising from chemotoxic species released from a GDF for radioactive waste and highlights potential difficulties associated with a lack of data being available with which to assess synergistic effects. It also highlights how such difficulties can be addressed.

Gynecological surgery and low back pain in older women: testing the association with sacroiliac joint stiffness and pelvic floor movements.

OBJECTIVE: To determine sacroiliac joint compliance characteristics and pelvic floor movements in older women relative to gynecological surgery history and back pain complaints. DESIGN: Single-visit laboratory measurement. SETTING: University clinical research center. PARTICIPANTS: Twenty-five women aged 65 years or older. OUTCOME MEASURES: Sacroiliac joint compliance measured by Doppler imaging of vibrations and ultrasound measures of pelvic floor motion during the active straight leg raise test. RESULTS: Doppler imaging of vibrations demonstrated test reliability ranging from 0.701 to 0.898 for detecting vibration on the ilium and sacrum sides of the sacroiliac joint. The presence of low-back pain or prior gynecological surgery was not significantly associated with a difference in the compliance or laxity symmetry of the sacroiliac joints. No significant difference in pelvic floor movement was found during the active straight leg raise test between subject groups. All P values were ≥.4159. CONCLUSIONS: Prior gynecological surgery and low-back pain were not significantly associated with side-to-side differences in the compliance of the sacroiliac joints or in significant changes in pelvic floor movement during a loading maneuver in a group of older women.

Decontamination of multiple casualties who are chemically contaminated: a challenge for acute hospitals.

Patients who have been contaminated by chemical compounds present a number of difficulties to emergency departments, in particular, the risk of secondary contamination of healthcare staff and facilities. The Department of Health in the United Kingdom has provided equipment to decontaminate chemically contaminated casualties who present at emergency departments. The capacity of this equipment is limited, and although both the ambulance and fire services have equipment to cope with mass casualties at the scene of a chemical incident, there is still the possibility that acute hospitals will be overwhelmed by large numbers of self-presenting patients. The risks and potential consequences of this gap in resilience are discussed and a number of possible practical solutions are proposed.

Single-dose immunogenicity and protective efficacy of simian adenoviral vectors against Plasmodium berghei.

Simian adenoviral vectors (SAd) offer an attractive alternative to standard human adenovirus serotype 5 (AdH5) subunit vaccination, due to pre-existing immunity affecting vaccine performance. We have used a mouse model of liver-stage malaria to test the efficiency of three chimpanzee-origin adenoviral vectors, AdC6, AdC7 and AdC9 containing ME.TRAP as an insert. AdC7 and AdC9 elicited strong immunogenicity ( approximately 20% of CD8(+) T cells in spleen), equivalent to or outperforming AdH5 and inducing sterile protection in 92% (C9), 83% (H5 and C7) and 67% (C6) of the mice, providing the first evidence of single-dose protection to Plasmodium berghei. Protection was afforded by the SAd despite high levels of pre-existing immunity to AdH5. Phenotypic analysis showed that all adenoviral vectors (Ad) elicited CD8(+) T cell responses with an effector memory T cell (T(EM)) phenotype. By contrast, vaccination with poxviral vectors did not confer protection to P. berghei and induced a predominantly CD8(+) central memory T cell (T(CM)) response. Multifunctional CD8(+) T cell responses (co-expressing IFN-gamma, TNF-alpha and IL-2) were also induced by the Ad in higher percentages than the poxviral vectors. Our data suggest that T(EM) cells are important as a first line of defense against fast-replicating pathogens such as murine Plasmodium and demonstrate the potential of replication-defective SAd as future malaria vaccines for humans.

Fatal cardiac arrhythmia after repeated exposure to 1,1-difluoroethane (DFE).

A 42-year-old man was found dead after repeated exposure to 1,1-difluoroethane (DFE, Freon 152a), a propellant found in CRC Duster, a product intended for the removal of dust and lint. Toxicologic analysis detected DFE in femoral blood 136.3 mg/L, brain 117.5 mg/kg, liver 87.6 mg/kg, lung 60.3 mg/kg, adipose 235.7 mg/kg, and vitreous fluid 25.1 mg/L. The cause of death was determined to be a fatal cardiac arrhythmia due to intoxication with 1,1-difluoroethane. After comparison to previously published cases involving DFE, we suggest that analysis of adipose tissue for DFE and similar compounds, along with blood and other tissues, may be useful in distinguishing between acute versus chronic exposure. Adipose may also be a valuable alternate specimen for detection in cases where loss or elimination from blood is likely to have occurred.

Evidence for the predominance of mid-tropospheric aerosols as subtropical anvil cloud nuclei.

NASA's recent Cirrus Regional Study of Tropical Anvils and Cirrus Layers-Florida Area Cirrus Experiment focused on anvil cirrus clouds, an important but poorly understood element of our climate system. The data obtained included the first comprehensive measurements of aerosols and cloud particles throughout the atmospheric column during the evolution of multiple deep convective storm systems. Coupling these new measurements with detailed cloud simulations that resolve the size distributions of aerosols and cloud particles, we found several lines of evidence indicating that most anvil crystals form on mid-tropospheric rather than boundary-layer aerosols. This result defies conventional wisdom and suggests that distant pollution sources may have a greater effect on anvil clouds than do local sources.

Fatal olanzapine-induced hyperglycemic ketoacidosis.

Olanzapine is an antipsychotic medication linked to the development, or exacerbation of, type 2 diabetes mellitus. This report describes 3 patients being treated with olanzapine who died suddenly and unexpectedly with hyperglycemic ketoacidosis. All had olanzapine concentrations within the therapeutic range. Vitreous glucose concentrations ranged from 640 mg/dL to 833 mg/dL, and blood acetone concentrations from 25.6 mg/dL to 57.6 mg/dL. Beta-hydroxybutyrate concentrations in blood were from 55.2 mg/dL to 110 mg/dL. Low levels of isopropanol were also detected. None had a history or family history of diabetes mellitus. Glycolated (A1C) hemoglobin in 2 cases was 14.3% and 14.7%. No predisposing factors to olanzapine-induced diabetes were identified. It is recommended that chemical testing of patients dying suddenly while being treated with antipsychotic drugs include vitreous glucose and blood acetone determinations to elucidate the cause and mechanism of death in these patients. Warnings concerning this potentially fatal complication of olanzapine therapy should be included in standard pharmaceutical and prescription references.