From the EBM pyramid to the Greek temple: a new conceptual approach to Guidelines as implementation tools in mental health.

Guideline methods to develop recommendations dedicate most effort around organising discovery and corroboration knowledge following the evidence-based medicine (EBM) framework. Guidelines typically use a single dimension of information, and generally discard contextual evidence and formal expert knowledge and consumer's experiences in the process. In recognition of the limitations of guidelines in complex cases, complex interventions and systems research, there has been significant effort to develop new tools, guides, resources and structures to use alongside EBM methods of guideline development. In addition to these advances, a new framework based on the philosophy of science is required. Guidelines should be defined as implementation decision support tools for improving the decision-making process in real-world practice and not only as a procedure to optimise the knowledge base of scientific discovery and corroboration. A shift from the model of the EBM pyramid of corroboration of evidence to the use of broader multi-domain perspective graphically depicted as 'Greek temple' could be considered. This model takes into account the different stages of scientific knowledge (discovery, corroboration and implementation), the sources of knowledge relevant to guideline development (experimental, observational, contextual, expert-based and experiential); their underlying inference mechanisms (deduction, induction, abduction, means-end inferences) and a more precise definition of evidence and related terms. The applicability of this broader approach is presented for the development of the Canadian Consensus Guidelines for the Primary Care of People with Developmental Disabilities.

A New Empirical Constraint on the Prevalence of Technological Species in the Universe.

UNLABELLED: In this article, we address the cosmic frequency of technological species. Recent advances in exoplanet studies provide strong constraints on all astrophysical terms in the Drake equation. Using these and modifying the form and intent of the Drake equation, we set a firm lower bound on the probability that one or more technological species have evolved anywhere and at any time in the history of the observable Universe. We find that as long as the probability that a habitable zone planet develops a technological species is larger than ∼10(-24), humanity is not the only time technological intelligence has evolved. This constraint has important scientific and philosophical consequences. KEY WORDS: Life-Intelligence-Extraterrestrial life. Astrobiology 2016, 359-362.

Economic evaluation in chronic pain: a systematic review and de novo flexible economic model.

There is unmet need in patients suffering from chronic pain, yet innovation may be impeded by the difficulty of justifying economic value in a field beset by data limitations and methodological variability. A systematic review was conducted to identify and summarise the key areas of variability and limitations in modelling approaches in the economic evaluation of treatments for chronic pain. The results of the literature review were then used to support the development of a fully flexible open-source economic model structure, designed to test structural and data assumptions and act as a reference for future modelling practice. The key model design themes identified from the systematic review included: time horizon; titration and stabilisation; number of treatment lines; choice/ordering of treatment; and the impact of parameter uncertainty (given reliance on expert opinion). Exploratory analyses using the model to compare a hypothetical novel therapy versus morphine as first-line treatments showed cost-effectiveness results to be sensitive to structural and data assumptions. Assumptions about the treatment pathway and choice of time horizon were key model drivers. Our results suggest structural model design and data assumptions may have driven previous cost-effectiveness results and ultimately decisions based on economic value. We therefore conclude that it is vital that future economic models in chronic pain are designed to be fully transparent and hope our open-source code is useful in order to aspire to a common approach to modelling pain that includes robust sensitivity analyses to test structural and parameter uncertainty.

Walking a tightrope: case management services and outpatient commitment.

Effective case managers in community mental health are successful at forging a working alliance with recipients. This article explores one key aspect of case management practice, serving involuntary clients, specifically those on outpatient commitment orders. In 19 intensive interviews, a subset of a larger study, case managers shared their perceptions of the utility of outpatient commitment with a focus on how such orders impacted the professional relationship. We argue that the use of advance psychiatric directives and shared decision-making processes can reduce the need for coercive practice.

All solid-state high power microwave source with high repetition frequency.

An all solid-state, megawatt-class high power microwave system featuring a silicon carbide (SiC) photoconductive semiconductor switch (PCSS) and a ferrimagnetic-based, coaxial nonlinear transmission line (NLTL) is presented. A 1.62 cm(2), 50 kV 4H-SiC PCSS is hard-switched to produce electrical pulses with 7 ns full width-half max (FWHM) pulse widths at 2 ns risetimes in single shot and burst-mode operation. The PCSS resistance drops to sub-ohm when illuminated with approximately 3 mJ of laser energy at 355 nm (tripled Nd:YAG) in a single pulse. Utilizing a fiber optic based optical delivery system, a laser pulse train of four 7 ns (FWHM) signals was generated at 65 MHz repetition frequency. The resulting electrical pulse train from the PCSS closely follows the optical input and is utilized to feed the NLTL generating microwave pulses with a base microwave-frequency of about 2.1 GHz at 65 MHz pulse repetition frequency (prf). Under typical experimental conditions, the NLTL produces sharpened output risetimes of 120 ps and microwave oscillations at 2-4 GHz that are generated due to damped gyromagnetic precession of the ferrimagnetic material's axially pre-biased magnetic moments. The complete system is discussed in detail with its output matched into 50 Ω, and results covering MHz-prf in burst-mode operation as well as frequency agility in single shot operation are discussed.

A compact 45 kV curve tracer with picoampere current measurement capability.

This paper discusses a compact high voltage curve tracer for high voltage semiconductor device characterization. The system sources up to 3 mA at up to 45 kV in dc conditions. It measures from 328 V to 60 kV with 15 V resolution and from 9.4 pA to 4 mA with 100 fA minimum resolution. Control software for the system is written in Microsoft Visual C# and features real-time measurement control and IV plotting, arc-protection and detection, an electrically isolated universal serial bus interface, and easy data exporting capabilities. The system has survived numerous catastrophic high voltage device-under-test arcing failures with no loss of measurement capability or system damage. Overall sweep times are typically under 2 min, and the curve tracer system was used to characterize the blocking performance of high voltage ceramic capacitors, high voltage silicon carbide photoconductive semiconductor switches, and high voltage coaxial cable.

Strategies for outcrossing and genetic manipulation of Drosophila compound autosome stocks.

Among all organisms, Drosophila melanogaster has the most extensive well-characterized collection of large-scale chromosome rearrangements. Compound chromosomes, rearrangements in which homologous chromosome arms share a centromere, have proven especially useful in genetic-based surveys of the entire genome. However, their potential has not been fully realized because compound autosome stocks are refractile to standard genetic manipulations: if outcrossed, they yield inviable aneuploid progeny. Here we describe two strategies, cold-shock and use of the bubR1 mutant alleles, to produce nullo gametes through nondisjunction. These gametes are complementary to the compound chromosome-bearing gametes and thus produce viable progeny. Using these techniques, we created a compound chromosome two C(2)EN stock bearing a red fluorescent protein-histone transgene, facilitating live analysis of these unusually long chromosomes.

There's more than meets the eye: the nuances of case management.

In this exploratory study, 50 mental health case managers from 2 Midwestern states were interviewed to capture their observations about the consumers they serve; aspects of the job they like and dislike; and their beliefs about the concept, process, and possibility of recovery from mental illness. The nature of the professional relationship in case management is described from the perspective of these professionals, as well as the methods these informants identify as key to the helping process. It is argued that effective case management requires complex and nuanced professional skills that might go unrecognized and underappreciated in community mental health.

Independent evolution of macrophage-tropism and increased charge between HIV-1 R5 envelopes present in brain and immune tissue.

BACKGROUND: Transmitted HIV-1 clade B or C R5 viruses have been reported to infect macrophages inefficiently, while other studies have described R5 viruses in late disease with either an enhanced macrophage-tropism or carrying envelopes with an increased positive charge and fitness. In contrast, our previous data suggested that viruses carrying non-macrophage-tropic R5 envelopes were still predominant in immune tissue of AIDS patients. To further investigate the tropism and charge of HIV-1 viruses in late disease, we evaluated the properties of HIV-1 envelopes amplified from immune and brain tissues of AIDS patients with neurological complications. RESULTS: Almost all envelopes amplified were R5. There was clear compartmentalization of envelope sequences for four of the five subjects. However, strong compartmentalization of macrophage-tropism in brain was observed even when brain and immune tissue envelope sequences were not segregated. R5 envelopes from immune tissue of four subjects carried a higher positive charge compared to brain envelopes. We also confirm a significant correlation between macrophage tropism and sensitivity to soluble CD4, a weak association with sensitivity to the CD4 binding site antibody, b12, but no clear relationship with maraviroc sensitivity. CONCLUSIONS: Our study shows that non-macrophage-tropic R5 envelopes carrying gp120s with an increased positive charge were predominant in immune tissue in late disease. However, highly macrophage-tropic variants with lower charged gp120s were nearly universal in the brain. These results are consistent with HIV-1 R5 envelopes evolving gp120s with an increased positive charge in immune tissue or sites outside the brain that likely reflect an adaptation for increased replication or fitness for CD4+ T-cells. Our data are consistent with the presence of powerful pressures in brain and in immune tissues selecting for R5 envelopes with very different properties; high macrophage-tropism, sCD4 sensitivity and low positive charge in brain and non-macrophage-tropism, sCD4 resistance and high positive charge in immune tissue.

Community-based mental health services: is coercion necessary?

In community mental health, limitation of service recipient choice and freedom takes place through mechanisms ranging from subtle to blatant. The justification of coercion in these settings typically focuses on recipient deficits. We argue that this focus must shift to the service system itself, and that the most successful efforts to improve recipient engagement will be those that support respectful provider-recipient relationships and the delivery of services that help recipients achieve goals of their choosing.

Long-range migration of intrinsic defects during irradiation or implantation.

A series of electron irradiations has been performed on diamond and 4H SiC single crystal specimens. A wide range of different doses and dose rates was investigated. In addition, a more limited investigation of localized hydrogen and helium implantation of 4H SiC has been made. The electron energies were sufficient to cause atomic displacements creating vacancies and self-interstitials in the irradiated samples. After electron-irradiation or implantation the samples were studied by low temperature (∼7 K) photoluminescence microscopy. It was found that some of the defect centres migrated over large distances outside of the irradiated regions and that this distance increased with increase of the dose. Two possible explanations for this remarkable behaviour are discussed. One is based on the absorption by the defects of light created by recombination of electrons and holes in the irradiated or implanted region. The other deals with the consequences of recombination-enhanced migration at point defects that traps carriers as they are driven out of the irradiated region by electric fields created during the irradiation or implantation process. Interstitial atoms are deduced as migrating further than vacancies in this process.

Wolbachia modification of sperm does not always require residence within developing sperm.

Wolbachia are maternally inherited intracellular bacteria known to manipulate the reproduction of their arthropod hosts. Wolbachia commonly affect the sperm of infected arthropods. Wolbachia-modified sperm cannot successfully fertilize unless the female is infected with the same Wolbachia type. A study of spermatogenesis in the parasitic wasp Nasonia vitripennis reveals that Wolbachia are not required in individual spermatocytes or spermatids to modify sperm. In N. vitripennis, Wolbachia modify nearly all sperm, but are found only in approximately 28% of developing sperm, and are also found in surrounding cyst and sheath cells. In the beetle Chelymorpha alternans, Wolbachia can modify up to 90% of sperm, but were never observed within the developing sperm or within the surrounding cyst cells; they were abundant within the outer testis sheath. We conclude that the residence within a developing sperm is not a prerequisite for Wolbachia-induced sperm modification, suggesting that Wolbachia modification of sperm may occur across multiple tissue membranes or act upstream of spermiogenesis.

Variation in HIV-1 R5 macrophage-tropism correlates with sensitivity to reagents that block envelope: CD4 interactions but not with sensitivity to other entry inhibitors.

BACKGROUND: HIV-1 R5 viruses cause most of the AIDS cases worldwide and are preferentially transmitted compared to CXCR4-using viruses. Furthermore, R5 viruses vary extensively in capacity to infect macrophages and highly macrophage-tropic variants are frequently identified in the brains of patients with dementia. Here, we investigated the sensitivity of R5 envelopes to a range of inhibitors and antibodies that block HIV entry. We studied a large panel of R5 envelopes, derived by PCR amplification without culture from brain, lymph node, blood and semen. These R5 envelopes conferred a wide range of macrophage tropism and included highly macrophage-tropic variants from brain and non-macrophage-tropic variants from lymph node. RESULTS: R5 macrophage-tropism correlated with sensitivity to inhibition by reagents that inhibited gp120:CD4 interactions. Thus, increasing macrophage-tropism was associated with increased sensitivity to soluble CD4 and to IgG-CD4 (PRO 542), but with increased resistance to the anti-CD4 monoclonal antibody (mab), Q4120. These observations were highly significant and are consistent with an increased affinity of envelope for CD4 for macrophage-tropic envelopes. No overall correlations were noted between R5 macrophage-tropism and sensitivity to CCR5 antagonists or to gp41 specific reagents. Intriguingly, there was a relationship between increasing macrophage-tropism and increased sensitivity to the CD4 binding site mab, b12, but decreased sensitivity to 2G12, a mab that binds a glycan complex on gp120. CONCLUSION: Variation in R5 macrophage-tropism is caused by envelope variation that predominantly influences sensitivity to reagents that block gp120:CD4 interactions. Such variation has important implications for therapy using viral entry inhibitors and for the design of envelope antigens for vaccines.

Lack of alternative coreceptor use by pediatric HIV-1 R5 isolates for infection of primary cord or adult peripheral blood mononuclear cells.

HIV-1 infection of neonates results in an extended acute period of virus replication, frequent neurological problems and reduced survival compared to adults. In adults, R5 viruses mainly infect CCR5(+) CD4(+) memory T-cells. In neonates, CCR5(+) memory T-cells form a substantially smaller fraction of total lymphocytes. We therefore tested whether alternative coreceptors confer infection of lymphocytes by pediatric isolates. Pediatric HIV-1 R5 isolates failed to replicate in Delta32/Delta32 CCR5 PBMCs or in cord PBMCs treated with a CCR5 inhibitor. These results do not indicate a role for alternative coreceptors and provide support for CCR5 inhibitors in the therapy of HIV-1(+) neonates.

Variation of macrophage tropism among HIV-1 R5 envelopes in brain and other tissues.

Human immunodeficiency virus (HIV)-positive individuals frequently suffer from progressive encephelopathy, which is characterized by sensory neuropathy, sensory myelopathy, and dementia. Our group and others have reported the presence of highly macrophage-tropic R5 variants of HIV-1 in brain tissue of patients with neurological complications. These variants are able to exploit low amounts of CD4 and/or CCR5 for infection and potentially confer an expanded tropism for any cell types that express low CD4 and/or CCR5. In contrast to the brain-derived envelopes, we found that envelopes from lymph node tissue, blood, or semen were predominantly non-macrophage-tropic and required high amounts of CD4 for infection. Nevertheless, where tested, the non-macrophage-tropic envelopes conferred efficient replication in primary CD4(+) T-cell cultures. Determinants of R5 macrophage tropism appear to involve changes in the CD4 binding site, although further unknown determinants are also involved. The variation of R5 envelopes also affects their sensitivity to inhibition by ligands and entry inhibitors that target CD4 and CCR5. In summary, HIV-1 R5 viruses vary extensively in macrophage tropism. In the brain, highly macrophage-tropic variants may represent neurotropic or neurovirulent viruses. In addition, variation in R5 macrophage tropism may also have implications (1) for transmission, depending on what role macrophages or cells that express low CD4 and/or CCR5 play in the establishment of infection in a new host, and (2) for pathogenesis and depletion of CD4(+) T cells (i.e., do highly macrophage-tropic variants confer a broader tropism among CD4(+) T-cell populations late in disease and contribute to their depletion?).

Non-macrophage-tropic human immunodeficiency virus type 1 R5 envelopes predominate in blood, lymph nodes, and semen: implications for transmission and pathogenesis.

Human immunodeficiency virus type 1 (HIV-1) R5 isolates that predominantly use CCR5 as a coreceptor are frequently described as macrophage tropic. Here, we compare macrophage tropism conferred by HIV-1 R5 envelopes that were derived directly by PCR from patient tissue. This approach avoids potentially selective culture protocols used in virus isolation. Envelopes were amplified (i) from blood and semen of adult patients and (ii) from plasma of pediatric patients. The phenotypes of these envelopes were compared to those conferred by an extended panel of envelopes derived from brain and lymph node that we reported previously. Our results show that R5 envelopes vary by up to 1,000-fold in their capacity to confer infection of primary macrophages. Highly macrophage-tropic envelopes were predominate in brain but were infrequent in semen, blood, and lymph node samples. We also confirmed that the presence of N283 in the C2 CD4 binding site of gp120 is associated with HIV-1 envelopes from the brain but absent from macrophage-tropic envelopes amplified from blood and semen. Finally, we compared infection of macrophages, CD4(+) T cells, and peripheral blood mononuclear cells (PBMCs) conferred by macrophage-tropic and non-macrophage-tropic envelopes in the context of full-length replication competent viral clones. Non-macrophage-tropic envelopes conferred low-level infection of macrophages yet infected CD4(+) T cells and PBMCs as efficiently as highly macrophage-tropic brain envelopes. The lack of macrophage tropism for the majority of the envelopes amplified from lymph node, blood, and semen is striking and contrasts with the current consensus that R5 primary isolates are generally macrophage tropic. The extensive variation in R5 tropism reported here is likely to have an important impact on pathogenesis and on the capacity of HIV-1 to transmit.