Clinical practice guidelines, psychotherapy and implications for psychiatry.

OBJECTIVE: The 2020 RANZCP clinical practice guidelines (CPG) for mood disorders, published in January 2021, raise important questions for practice and teaching. The objective of this review is to critically appraise the content of the CPG to examine if it reflects contemporary practice-based evidence. CONCLUSION: Our review identifies factual error and notes international criticism. Retraction and amendment of the CPG is needed, particularly in the current political climate.

Nationally Informed Recommendations on Approaching the Detection, Assessment, and Management of Mild Cognitive Impairment.

Prior to the usual clinical symptoms of dementia, there can be subtle changes in cognitive function that differ from the normal age-related cognitive decline, which has been termed mild cognitive impairment (MCI). The increase in the numbers of individuals with possible MCI presenting to health care professionals, notably, General Practitioners (GPs), is going to rise dramatically in the coming years. With ever increasing demands on GPs, it is therefore timely to provide information that can be accessed by health care professionals to assist them in making appropriate diagnoses and to provide the most relevant, evidence-based treatment options. We have provided a comprehensive list of recommendations that aim to address key aspects of MCI in primary care. Specifically, these relate to detection and diagnosis; sharing the diagnosis, monitoring, and follow up; practical interventions to potentially delay progression; and personalizing care-planning, engagement, and patient motivation for the long term.

Introduction to the special issue on supersonic jet noise.

This editorial's goals are (1) to highlight a few key developments in supersonic jet and launch vehicle noise research over the past several decades while describing some of the critical modern requirements facing government and industry organizations and (2) to summarize the contributions of the articles in this Supersonic Jet Noise special issue in the context of these developments and requirements.

The biomechanical significance of the elongated rodent incisor root in the mandible during incision.

Rodents are characterised by a distinctive masticatory apparatus which includes a single pair of enlarged and continually growing incisors. This morphology, termed diprotodonty, has also independently evolved in a number of other mammals, including the aye-aye. This study examined the functional significance of the internal "root" of the elongated rodent-like incisor. The mandibles of four rodents and an aye-aye were modelled to exhibit incrementally shorter incisor roots. Finite element analysis was used to predict stress and strain patterns across the jaw to determine whether the length of the incisor root contributes to the resistance of mechanical forces encountered in the mandible during incision. It was found that von Mises stresses increase in the region of the mandible local to where the incisor is removed, but that the stress distribution across the wider mandible is only minimally affected. Thus, the long internal incisor appears to play a small role in resisting bending forces close to the incisor alveolus, and may act with the arch-like mandibular shape to strengthen the mandible in this region. However, the impact across the whole mandible is relatively limited, suggesting the highly elongate incisor in diprotodont mammals may be principally driven by other factors such as rapid incisor wear.

Steady active control of noise radiation from highly heated supersonic jets.

The goal of the present investigation is to study the effect of using fluid inserts for noise control at high exhaust temperatures by performing a sequence of large eddy simulations on a typical military-style nozzle, both with and without fluid inserts, at jet inlet total temperature ratios of 2.5, 5, and 7. An exact physics-based splitting of the jet flow-field into its hydrodynamic, acoustic, and thermal components reveals clear evidence of a reduction in the radiation efficiency of Mach waves from the controlled jet. This effect is far more pronounced at afterburner conditions, where the location of the maximum noise reduction is observed to shift upstream with increase in jet temperature, thus matching the maximum location of the jet OASPL directivity. Moreover, the maximum noise reduction achieved at afterburner conditions exceeds that obtained at lower exhaust temperatures. This is encouraging and shows that the effectiveness of the fluid inserts improves with an increase in jet exhaust temperature. Furthermore, by accounting for the effect of bleeding off bypass air for the fluid inserts in the LES simulation, this noise reduction is predicted to be achieved at a conservative thrust loss estimate of under 2% at both laboratory and afterburner operating conditions.

Pharmacological management of post-traumatic stress disorder and its associated nightmares: A survey of psychiatrists.

WHAT IS KNOWN AND OBJECTIVE: To describe the pharmacological management of post-traumatic stress disorder (PTSD) by psychiatrists, with a focus on their use of clinical guidelines and the role of prazosin for nightmares. METHODS: An online survey of Australian and New Zealand psychiatrists was conducted. Aspects included respondent demographics, familiarity and usage of guidelines for PTSD, and opinions on the safety and efficacy of prazosin for PTSD-associated nightmares. RESULTS AND DISCUSSION: A total of 157 responses were recorded, 106 of which were complete. The most frequently used guideline for PTSD management was over 10 years old and used by only 48% of respondents. Peer-reviewed scientific journals were the most common additional source used by psychiatrists to inform their practice. For the targeted treatment of nightmares, 35 different medications had been trialled by respondents. Prazosin had been prescribed by 86% of psychiatrists for PTSD-associated nightmares, with only 2% reporting it to be ineffective in reducing nightmare frequency and/or intensity. Psychiatrists who were familiar with prazosin-mentioning guidelines (P < .05) and those who more frequently treat patients with PTSD (P < .01) were most likely to have prescribed prazosin. WHAT IS NEW AND CONCLUSION: Psychiatrists generally do not rely on guidelines to inform the treatment of PTSD. Off-label prescription of prazosin for PTSD-associated nightmares occurs frequently, with positive perceived outcomes, despite conflicting published evidence and a lack of local guideline recommendations for its use.

Informed consent and childhood gender dysphoria: emerging complexities in diagnosis and treatment.

OBJECTIVE: To explore some of the emerging complexities in the management of childhood gender dysphoria. CONCLUSION: The authors raise questions about the gender-affirmation approach and highlight concerns about informed consent and research ethics.

Effect of fluid injection on turbulence and noise reduction of a supersonic jet.

Supersonic jets, such as the ones used in high-performance military aircraft, have both downstream and upstream noise components due to the large-scale turbulent structures and the presence of shock cells in the jet plume. The fluid insert technology is a noise reduction method that has been shown to effectively reduce both these noise components. This paper analyses the unsteady flow changes associated with different fluid insert configurations with a goal of helping to understand the detailed noise reduction mechanisms. Using direct cross-correlations of the near-field data with the far-field microphone signals, it is found that even the use of a single injector as a fluid insert helps break up the large-scale structures of the flow. However, a more azimuthally distributed blowing is required to reduce the upstream broadband shock-associated noise (BBSAN). Addition of upstream injectors at each azimuthal location further enhances the BBSAN reduction. Decomposition of the jet flow-field into hydrodynamic and acoustic modes shows that fluid insert nozzles reduce the amplitude and convection speed of the coherent acoustic mode in the plane of highest noise reduction. This article is part of the theme issue 'Frontiers of aeroacoustics research: theory, computation and experiment'.

Mechanical significance of morphological variation in diprotodont incisors.

All rodents possess a single pair of enlarged incisors that grow throughout life. This condition (diprotodonty) is characteristic of Rodentia, but is also found in other mammals such as lagomorphs, hyraxes, the aye-aye and common wombat. This study surveyed lower incisor morphology across extant diprotodonts to examine shape variation within and between rodents and other diprotodonts, and to determine if tooth shape varies in a manner predictable from mechanics. Six linear and area variables were recorded from microCT scans of the mandibles of 33 diprotodont mammals. The curvature of the rodent lower incisors, as measured by the proportion of a circle it occupies, was shown to vary between 20 and 45%, with non-Glires taxa falling outside this range. Relative lengths of the portions of the incisor within and external to the mandible were not significantly correlated when the overall size was taken into account. Cross-sectional geometry of the incisor was significantly correlated with the external length of the incisor. Overall, incisor morphology was shown to vary in a way predictable from ecology and mechanics, in order to resist bending. Among non-rodents, lagomorph incisors closely resemble those of rodents, and, relative to rodents, hyrax and wombat incisors are somewhat smaller but aye-aye incisors are much more extreme in morphology.

Convergent evolution in the Euarchontoglires.

Convergence-the independent evolution of similar phenotypes in distantly related clades-is a widespread and much-studied phenomenon. An often-cited, but hitherto untested, case of morphological convergence is that between the aye-aye and squirrels. The aye-aye (Daubentonia madagascariensis) is a highly unusual lemuriform primate that has evolved a dentition similar to that of rodents: it possesses large, ever-growing incisors which it uses to strip the bark from trees in order to feed on wood-boring beetle larvae. Indeed, such is the similarity that some of the earliest classifications of the aye-aye placed it in the squirrel genus Sciurus Here, we aimed to test the degree of convergence between the skulls and lower jaws of squirrels and the aye-aye. Three-dimensional landmarks were recorded from the crania and mandibles of 46 taxa representing the majority of families in the Euarchontoglires. Results were plotted as phylomorphospaces and convergence measures were calculated. The convergence between squirrels and the aye-aye was shown to be statistically significant for both the cranium and mandible, although the mandibles seem to converge more closely in shape. The convergence may indicate strong functional drivers of morphology in these taxa, i.e. the use of the incisors to produce high bite forces during feeding. Overall, we have shown that this classic case of convergence stands up to quantitative analysis.

Posttraumatic Stress Disorder, Antipsychotic Use and Risk of Dementia in Veterans.

OBJECTIVES: To examine the risk of dementia associated with posttraumatic stress disorder (PTSD) and the contribution of antipsychotic use to this risk. DESIGN: Retrospective cohort study SETTING: Australia. Administrative claims data from the Australian Government Department of Veterans' Affairs were used. PARTICIPANTS: Male Vietnam veterans aged 55 to 65 at baseline (2001-02) with no preexisting dementia diagnosis (N = 15,612). MEASUREMENTS: The association between PTSD and dementia was assessed over 12 years of follow-up. Dementia was identified as a hospital diagnosis, dementia record in service disability data, or dispensing of medicines for dementia. Cox-proportional hazards models were used, with age as the time-scale. Results were stratified according to baseline antipsychotic use. RESULTS: No greater risk of dementia was observed with PTSD. In veterans who received antipsychotics, dementia risk was significantly higher than in those who did not (hazard ratio (HR) = 2.1, 95% confidence interval (CI) = 1.4-3.3). Dementia risk was significantly greater in veterans hospitalized for PTSD who received antipsychotics (HR = 2.2, 95% CI = 1.1-4.6) and veterans without PTSD who received antipsychotics (HR = 4.3, 95% CI = 2.1-8.6) than in those without PTSD with no antipsychotic use. CONCLUSION: Antipsychotic use may be a contributor to dementia risk. These findings should be interpreted with caution because the study design was observational. Further research using prospective study designs in settings where diagnostic data, cognitive function, and disease severity are available are required.

fMRI responses to Jung's Word Association Test: implications for theory, treatment and research.

Jung's Word Association Test was performed under fMRI conditions by 12 normal subjects. Pooled complexed responses were contrasted against pooled neutral ones. The fMRI activation pattern of this generic 'complexed response' was very strong (corrected Z scores ranging from 4.90 to 5.69). The activation pattern in each hemisphere includes mirror neurone areas that track 'otherness' (perspectival empathy), anterior insula (both self-awareness and emotional empathy), and cingulated gyrus (self-awareness and conflict-monitoring). These are the sites described by Siegel and colleagues as the 'resonance circuitry' in the brain which is central to mindfulness (awareness of self) and empathy (sense of the other), negotiations between self awareness and the 'internal other'. But there is also an interhemispheric dialogue. Within 3 seconds, the left hemisphere over-rides the right (at least in our normal subjects). Mindfulness and empathy are central to good psychotherapy, and complexes can be windows of opportunity if left-brain hegemony is resisted. This study sets foundations for further research: (i) QEEG studies (with their finer temporal resolution) of complexed responses in normal subjects (ii) QEEG and fMRI studies of complexed responses in other conditions, like schizophrenia, PTSD, disorders of self organization.

Potent orally bioavailable purine nucleoside phosphorylase inhibitor BCX-4208 induces apoptosis in B- and T-lymphocytes--a novel treatment approach for autoimmune diseases, organ transplantation and hematologic malignancies.

The profound suppression of T-cell immunity seen in purine nucleoside phosphorylase (PNP; EC 2.4.2.1) deficient patients supports potential application of inhibitors of PNP in the therapy of T-cell mediated diseases. BCX-4208 is a novel potent transition state analog inhibitor of human PNP with an IC(50) of 0.5 nM. PNP inhibition leads to elevation of dGuo which is converted to dGTP mainly in lymphocytes causing imbalance in deoxynucleotide (dNTP) pools and cell apoptosis. In in vitro studies, neither BCX-4208 nor dGuo alone inhibits proliferation of lymphocytes. BCX-4208 in the presence of 10 microM deoxyguanosine (dGuo) inhibits lymphocyte proliferation induced by MLR, IL-2 or Con A with IC(50)s of 0.159, 0.26 and 0.73 microM, respectively. The IC(50) for dGuo in the presence of 1 microM BCX-4208 for the IL-2 stimulated lymphocytes was 3.12 microM. dGTP in human lymphocytes is elevated and a 3-5 fold increase in dGTP results in 50% inhibition after in vitro exposure to BCX-4208 and dGuo. Flow cytometric analyses of human lymphocytes using annexin V staining reveal that BCX-4208 in the presence of dGuo induces cellular apoptosis in T-cells (CD3+), B-cells (CD20+, CD19+) and NK (CD56+) cells. BCX-4208 is orally bioavailable in mice and elevates plasma dGuo levels to 3.7 microM (predose levels<0.004 microM), similar to levels seen in PNP-deficient patients and levels needed to cause apoptosis in T and B-cells. These data support the evaluation of BCX-4208 in the treatment of T-cell and B-cell mediated diseases. BCX-4208 is currently undergoing early clinical investigation in psoriasis and gout.

A three dimensional parabolic equation method for sound propagation in moving inhomogeneous media.

In this paper, a formulation of the Helmholtz equation for three dimensional sound propagation in a moving inhomogeneous medium in cylindrical coordinates is derived. Based on this formulation, a three dimensional parabolic equation (PE) is constructed. This PE can be used to model sound propagation in an inhomogeneous arbitrary moving medium. The method is used here to simulate three dimensional outdoor sound propagation above a rigid flat ground surface. The numerical results for two simple wind cases are presented and compared with analytical results to validate the methodology. Examples of propagation problems with more complicated wind are then included to demonstrate the importance of including the wind velocity directly in the PE method.

Synthesis of analogs of forodesine HCl, a human purine nucleoside phosphorylase inhibitor-Part I.

Forodesine HCl is being investigated as a potential therapeutic target for the control of T-cell proliferation. During our ongoing process development work on forodesine HCl several novel compounds were identified as possible impurities in the process. Herein we present the synthesis of three novel compounds (2-4).

Synthesis of labeled BCX-4208, a potent inhibitor of purine nucleoside phosphorylase.

BCX-4208, a novel inhibitor of the enzyme purine nucleoside phosphorylase, mimics the charged ribosyl oxocarbenium ion formed during the transition state of the enzyme-catalyzed C-N bond cleavage of nucleosides. A slow-onset, tight-binding inhibitor with a Ki(*) of 16 +/- 1.4 pM, BCX-4208 is one of the most potent inhibitors known for the enzyme. In support of our BCX-4208 clinical program, a mass spectrometric assay has been developed that required labeled BCX-4208 as an internal standard. The synthesis of [(2)H](2)-BCX-4208 and [(13)C]-BCX-4208 is described in this report.

Open trial of interpersonal psychotherapy for chronic post traumatic stress disorder.

OBJECTIVE: The aim of this study was to investigate the feasibility of adapting group-based interpersonal psychotherapy (IPT-G) for patients with chronic post traumatic stress disorder (PTSD). METHODS: Thirteen subjects with DSM-IV-defined PTSD, with symptom duration greater than 12 months, entered the study, an 8-week treatment programme conducted in a clinical setting using IPT-G modified for the treatment of PTSD. Data obtained were analysed qualitatively and quantitatively. RESULTS: All 13 subjects completed the treatment programme and showed significant improvement in social functioning, general wellbeing and depressive symptoms. Treatment completers demonstrated a moderate reduction in the avoidant symptom cluster of PTSD. These improvements appeared stable at 3-month follow-up. Benefits appeared to be associated with perceived intra-therapy progress in resolving identified IPT problem areas. Qualitative analysis found that themes of 'reconnection' and 'interpersonal efficacy' were core parts of the experience of the treatment. CONCLUSION: IPT-G modified for PTSD appears to be of modest symptomatic benefit, but may lead to improvement in social functioning, general psychological wellbeing and enhanced interpersonal functioning. Further studies are indicated.