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.

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.

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.

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.

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'.

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.

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.

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.

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).

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.

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.

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.

Abnormal frontal and parietal activity during working memory updating in post-traumatic stress disorder.

This study used event-related potentials (ERPs) to investigate the timing and scalp topography of working memory in post-traumatic stress disorder (PTSD). This study was designed to investigate ERPs associated with a specific working memory updating process. ERPs were recorded from 10 patients and 10 controls during two visual tasks where (a) targets were a specific word or (b) targets were consecutive matching words. In the first task, nontarget words are not retained in working memory. In the second task, as in delay-match-to-sample tasks, a non-target word defines a new target identity, so these words are retained in working memory. This working memory updating process was related to large positive ERPs over frontal and parietal areas at 400-800 ms, which were smaller in PTSD. Estimation of cortical source activity indicated abnormal patterns of frontal and parietal activity in PTSD, which were also observed in regional cerebral blood flow [Clark, C.R., McFarlane, A.C., Morris, P., Weber, D.L., Sonkkilla, C., Shaw, M., Marcina, J., Tochon-Danguy, H., Egan, G., 2003. Cerebral function in posttraumatic stress disorder during verbal working memory updating: a positron emission tomography study. Biological Psychiatry 53, 474-481]. Frontal and parietal cortex are known to be involved in distributed networks for working memory processes, interacting with medial temporal areas during episodic memory processes. Abnormal function in these brain networks helps to explain everyday concentration and memory difficulties in PTSD.

Synthesis and pharmacokinetic and pharmacodynamic evaluation of the forodesine HCl analog BCX-3040.

Forodesine HCl is a potent inhibitor of the enzyme purine nucleoside phosphorylase (PNP) and is currently in clinical trials for the treatment of leukemia and lymphoma. Animal models indicated that forodesine HCl would have low oral bioavailability in humans and it was initially developed as an intravenous formulation. We were interested in identifying analogs of forodesine HCl with improved oral bioavailability. The 2'-deoxy analog (BCX-3040) was synthesized and its pharmacokinetic and pharmacodynamic properties compared with forodesine HCl.

Cerebral function in posttraumatic stress disorder during verbal working memory updating: a positron emission tomography study.

BACKGROUND: This study examined cerebral function in posttraumatic stress disorder (PTSD) during the updating of working memory to trauma-neutral, verbal information. METHODS: Ten PTSD and matched control subjects completed a visuoverbal target detection task involving continuous updating (Variable target condition) or no updating (Fixed target condition) of target identity, with updating activity estimated by condition comparison. RESULTS: Normal updating activity using this paradigm involved bilateral activation of the dorsolateral prefrontal cortex (DLPFC) and inferior parietal lobe. The PTSD group lacked this activation in the left hemisphere and was significantly different from control subjects in this regard, but showed additional activation in the superior parietal lobe, bilaterally. CONCLUSIONS: The pattern of parietal activation suggests a dependence on visuospatial coding for working memory representation of trauma-neutral, verbal information. Group differences in the relative involvement of the DLPFC indicate less dependence in PTSD on the executive role normally attributed to the left DLPFC for monitoring and manipulation of working memory content in posterior regions of the brain.

Efficacy of sertraline in a 12-week trial for generalized anxiety disorder.

OBJECTIVE: Sertraline's efficacy and tolerability in treating generalized anxiety disorder were evaluated. METHOD: Adult outpatients with DSM-IV generalized anxiety disorder and a total score of 18 or higher on the Hamilton Anxiety Rating Scale were eligible. After a 1-week single-blind placebo lead-in, patients were randomly assigned to 12 weeks of double-blind treatment with placebo (N=188, mean baseline anxiety score=25) or flexible doses (50-150 mg/day) of sertraline (N=182, mean anxiety score=25). The primary outcome measure was baseline-to-endpoint change in the Hamilton anxiety scale total score. A secondary efficacy measure was the Clinical Global Impression (CGI) improvement score; response was defined as a score of 2 or less. RESULTS: Sertraline patients had significantly greater improvement than placebo patients on all efficacy measures at week 4. Analysis of covariance of the intent-to-treat group at endpoint (with the last observation carried forward) showed a significant difference in the decrease from baseline of the least-square mean total score on the Hamilton anxiety scale between sertraline (mean=11.7) and placebo (mean=8.0). Significantly greater endpoint improvement with sertraline than placebo was obtained for mean scores on the Hamilton anxiety scale psychic factor (6.7 versus 4.1) and somatic factor (5.0 versus 3.9). The rate of responders, based on CGI improvement and last observation carried forward, was significantly higher for sertraline (63%) than placebo (37%). Sertraline was well tolerated; 8% of patients versus 10% for placebo dropped out because of adverse events. CONCLUSIONS: Sertraline appears to be efficacious and well tolerated in the treatment of generalized anxiety disorder.

Synthesis of a potent transition-state inhibitor of 5'-deoxy-5'-methylthioadenosine phosphorylase.

Human 5'-deoxy-5'-methylthioadenosine phosphorylase (MTAP) participates in the purine salvage pathway to generate adenine and methylthioribose-1-phosphate, which in turn is converted into adenine nucleotides and methionine. Hence, inhibition of MTA phosphorylase may be an effective target in the design of potential antiproliferative agents. Presented herein is the synthesis of 2-(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5-methylsulfanylmethylpyrrolidin-3,4-diol (1), a potent inhibitor of MTAP.

Blunted growth hormone response to clonidine in post-traumatic stress disorder.

Hyperactivity of the sympathetic and noradrenergic systems is thought to be a feature of post-traumatic stress disorder (PTSD). Assessment of noradrenergic receptor function can be undertaken by measuring the growth hormone (GH) response to the alpha2-agonist clonidine. The aim of this study was to examine whether subjects with combat-related PTSD (with or without co-morbid depression) have a blunted growth hormone response to clonidine, compared to a combat-exposed control group. Twenty-three Vietnam veterans suffering from PTSD alone, 27 suffering from PTSD and co-morbid depression, and 32 veteran controls with no psychiatric illness were administered 1.5 microg/kg clonidine i.v. Plasma growth hormone was measured every 20 min for 120 min. The growth hormone response to clonidine was significantly blunted in the non-depressed PTSD group compared to both the depressed PTSD group and the control group as measured by peak growth hormone, delta growth hormone and AUC growth hormone. Subjects with PTSD and no co-morbid depressive illness show a blunted growth hormone response to clonidine. This suggests that post-synaptic alpha2-receptors are subsensitive. This finding is consistent with other studies showing increased noradrenergic activity in PTSD.