BackgroundFibromyalgia is a chronic widespread pain condition a ecting millions of people worldwide. Current pharmacotherapies are o en ine ective and poorly tolerated. Combining di erent agents could provide superior pain relief and possibly also fewer side e ects. ObjectivesTo assess the e icacy, safety, and tolerability of combination pharmacotherapy compared to monotherapy or placebo, or both, for the treatment of fibromyalgia pain in adults. Search methodsWe searched CENTRAL, MEDLINE, and Embase to September 2017. We also searched reference lists of other reviews and trials registries. Selection criteriaDouble-blind, randomised controlled trials comparing combinations of two or more drugs to placebo or other comparators, or both, for the treatment of fibromyalgia pain. Data collection and analysisFrom all studies, we extracted data on: participant-reported pain relief of 30% or 50% or greater; patient global impression of clinical change (PGIC) much or very much improved or very much improved; any other pain-related outcome of improvement; withdrawals (lack of e icacy, adverse events), participants experiencing any adverse event, serious adverse events, and specific adverse events (e.g. somnolence and dizziness). The primary comparison was between combination and one or all single-agent comparators. We also assessed the evidence using GRADE and created a 'Summary of findings' table. Main resultsWe identified 16 studies with 1474 participants. Three studies combined a non-steroidal anti-inflammatory drug (NSAID) with a benzodiazepine (306 participants); two combined amitriptyline with fluoxetine (89 participants); two combined amitriptyline with a di erent agent (92 participants); two combined melatonin with an antidepressant (164 participants); one combined carisoprodol, paracetamol (acetaminophen), and ca eine (58 participants); one combined tramadol and paracetamol (acetaminophen) (315 participants); one combined malic acid and magnesium (24 participants); one combined a monoamine oxidase inhibitor with 5hydroxytryptophan (200 participants); and one combined pregabalin with duloxetine (41 participants). Six studies compared the combination of multiple agents with each component alone and with inactive placebo; three studies compared combination Combination pharmacotherapy for the treatment of fibromyalgia in adults (Review)

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Androgen-dependent urinary constituents from males hasten reproductive maturation (the Vandenbergh effect) and disrupt periimplantation pregnancy (the Bruce effect) in nearby females. Each of these effects can be mimicked in socially isolated females by direct administration of exogenous oestrogens. The current experiments were designed to determine the role of males' urinary 17b-oestradiol (E 2 ) in their capacities to induce these effects. A preliminary experiment showed that both males on a phyto-oestrogen-rich soy-based diet and those on a phyto-oestrogen-free diet could induce both effects. For subsequent experiments, males were castrated and treated with either oil vehicle or E 2 . Enzyme immunoassay was conducted on non-invasively collected urine samples from these males. Concentrations of urinary testosterone were subnormal in both conditions, but urinary E 2 was restored to the normal range for intact males in castrates given E 2 . Urinary creatinine was also quantified as a measure of hydration and was significantly reduced in males treated with E 2 . Castration diminished the capacity of males to promote growth of the immature uterus and also their capacity to disrupt blastocyst implantation in inseminated females. Injections of E 2 to castrated males restored both capacities. These data converge with other studies indicating that E 2 is the main constituent of male urine responsible for induction of both the Vandenbergh and the Bruce effects.

In studies of stress, it can be difficult to obtain blood rapidly enough to avoid confounding steroid measures. Noninvasive urinary steroid measures may provide an alternative insofar as they reflect systemic steroids. In Experiment 1, we profiled urinary corticosterone, progesterone, and estradiol in ovariectomized female mice following 1 h on an elevated platform. This increased urinary corticosterone for 3 h and progesterone for 4 h. In Experiment 2, blood and urine samples were obtained at 0-6 h following stressor offset. Females showed increased serum corticosterone and progesterone immediately after stressor offset. Urinary corticosterone was increased at both 0 and 2 h post-stress, while an increase in progesterone 2-6 h after stressor offset was not significant. Estradiol was not influenced by this mild stressor. In Experiment 3, mice were exposed to a more severe 1 h stressor, a rat across a wire-mesh grid. In serum, both corticosterone and progesterone were elevated immediately after stressor offset and returned to baseline within 2 h. In urine, this severe stressor elevated corticosterone immediately and 2 h after stressor offset, and in progesterone 2 h after stressor offset. Estradiol in serum was not dynamic, but it was significantly elevated in urine 4 h after stressor offset. Urinary measures generally reflected systemic measures; however, with a different time course resulting in a longer return to baseline. We suggest that the relative value of serum or urinary steroid measures in mice depends upon the experimental design, and that estradiol may only respond when the stressor is severe.

Defense and security organizations depend upon science and technology to meet operational needs, predict and counter threats, and meet increasingly complex demands of modern warfare. Artificial intelligence and robotics could provide solutions to a wide range of military gaps and deficiencies. At the same time, the unique and rapidly evolving nature of AI and robotics challenges existing polices, regulations, and values, and introduces complex ethical issues that might impede their development, evaluation, and use by the Canadian Armed Forces (CAF). Early consideration of potential ethical issues raised by military use of emerging AI and robotics technologies in development is critical to their effective implementation. This article presents an ethics assessment framework for emerging AI and robotics technologies. It is designed to help technology developers, policymakers, decision makers, and other stakeholders identify and broadly consider potential ethical issues that might arise with the military use and integration of emerging AI and robotics technologies of interest. We also provide a contextual environment for our framework, as well as an example of how our framework can be applied to a specific technology. Finally, we briefly identify and address several pervasive issues that arose during our research.