Subcortical volumetric abnormalities in bipolar disorder.

Considerable uncertainty exists about the defining brain changes associated with bipolar disorder (BD). Understanding and quantifying the sources of uncertainty can help generate novel clinical hypotheses about etiology and assist in the development of biomarkers for indexing disease progression and prognosis. Here we were interested in quantifying case-control differences in intracranial volume (ICV) and each of eight subcortical brain measures: nucleus accumbens, amygdala, caudate, hippocampus, globus pallidus, putamen, thalamus, lateral ventricles. In a large study of 1710 BD patients and 2594 healthy controls, we found consistent volumetric reductions in BD patients for mean hippocampus (Cohen's d=-0.232; P=3.50 × 10-7) and thalamus (d=-0.148; P=4.27 × 10-3) and enlarged lateral ventricles (d=-0.260; P=3.93 × 10-5) in patients. No significant effect of age at illness onset was detected. Stratifying patients based on clinical subtype (BD type I or type II) revealed that BDI patients had significantly larger lateral ventricles and smaller hippocampus and amygdala than controls. However, when comparing BDI and BDII patients directly, we did not detect any significant differences in brain volume. This likely represents similar etiology between BD subtype classifications. Exploratory analyses revealed significantly larger thalamic volumes in patients taking lithium compared with patients not taking lithium. We detected no significant differences between BDII patients and controls in the largest such comparison to date. Findings in this study should be interpreted with caution and with careful consideration of the limitations inherent to meta-analyzed neuroimaging comparisons.

The neural basis of flashback formation: the impact of viewing trauma.

BACKGROUND: Psychological traumatic events, such as war or road traffic accidents, are widespread. A small but significant proportion of survivors develop post-traumatic stress disorder (PTSD). Distressing, sensory-based involuntary memories of trauma (henceforth 'flashbacks') are the hallmark symptom of PTSD. Understanding the development of flashbacks may aid their prevention. This work is the first to combine the trauma film paradigm (as an experimental analogue for flashback development) with neuroimaging to investigate the neural basis of flashback aetiology. We investigated the hypothesis that involuntary recall of trauma (flashback) is determined during the original event encoding. Method A total of 22 healthy volunteers viewed a traumatic film whilst undergoing functional magnetic resonance imaging (fMRI). They kept a 1-week diary to record flashbacks to specific film scenes. Using a novel prospective fMRI design, we compared brain activation for those film scenes that subsequently induced flashbacks with both non-traumatic control scenes and scenes with traumatic content that did not elicit flashbacks ('potentials'). RESULTS: Encoding of scenes that later caused flashbacks was associated with widespread increases in activation, including in the amygdala, striatum, rostral anterior cingulate cortex, thalamus and ventral occipital cortex. The left inferior frontal gyrus and bilateral middle temporal gyrus also exhibited increased activation but only relative to 'potentials'. Thus, these latter regions appeared to distinguish between traumatic content that subsequently flashed back and comparable content that did not. CONCLUSIONS: Results provide the first prospective evidence that the brain behaves differently whilst experiencing emotional events that will subsequently become involuntary memories - flashbacks. Understanding the neural basis of analogue flashback memory formation may aid the development of treatment interventions for this PTSD feature.

Neuropsychological testing of cognitive impairment in euthymic bipolar disorder: an individual patient data meta-analysis.

OBJECTIVE: An association between bipolar disorder and cognitive impairment has repeatedly been described, even for euthymic patients. Findings are inconsistent both across primary studies and previous meta-analyses. This study reanalysed 31 primary data sets as a single large sample (N = 2876) to provide a more definitive view. METHOD: Individual patient and control data were obtained from original authors for 11 measures from four common neuropsychological tests: California or Rey Verbal Learning Task (VLT), Trail Making Test (TMT), Digit Span and/or Wisconsin Card Sorting Task. RESULTS: Impairments were found for all 11 test-measures in the bipolar group after controlling for age, IQ and gender (Ps ≤ 0.001, E.S. = 0.26-0.63). Residual mood symptoms confound this result but cannot account for the effect sizes found. Impairments also seem unrelated to drug treatment. Some test-measures were weakly correlated with illness severity measures suggesting that some impairments may track illness progression. CONCLUSION: This reanalysis supports VLT, Digit Span and TMT as robust measures of cognitive impairments in bipolar disorder patients. The heterogeneity of some test results explains previous differences in meta-analyses. Better controlling for confounds suggests deficits may be smaller than previously reported but should be tracked longitudinally across illness progression and treatment.

Development of an evidence-informed leisure time physical activity resource for adults with spinal cord injury: the SCI Get Fit Toolkit.

OBJECTIVES: To systematically develop an evidence-informed leisure time physical activity (LTPA) resource for adults with spinal cord injury (SCI). SETTING: Canada. METHODS: The Appraisal of Guidelines, Research and Evaluation (AGREE) II protocol was used to develop a toolkit to teach and encourage adults with SCI how to make smart and informed choices about being physically active. A multidisciplinary expert panel appraised the evidence and generated specific recommendations for the content of the toolkit. Pilot testing was conducted to refine the toolkit's presentation. RESULTS: Recommendations emanating from the consultation process were that the toolkit be a brief, evidence-based resource that contains images of adults with tetraplegia and paraplegia, and links to more detailed online information. The content of the toolkit should include the physical activity guidelines (PAGs) for adults with SCI, activities tailored to manual and power chair users, the benefits of LTPA, and strategies to overcome common LTPA barriers for adults with SCI. The inclusion of action plans and safety tips was also recommended. CONCLUSION: These recommendations have resulted in the development of an evidence-informed LTPA resource to assist adults with SCI in meeting the PAGs. This toolkit will have important implications for consumers, health care professionals and policy makers for encouraging LTPA in the SCI community.

Orthodontic manpower requirements of Trinidad and Tobago.

OBJECTIVE: A study was done to estimate the orthodontic manpower requirements of Trinidad and Tobago. METHODS: A questionnaire was administered via e-mail to 9 of 11 orthodontists. Information from a population census, a report on the orthodontic treatment needs of children in Trinidad and Tobago and this questionnaire were used to calculate the number of orthodontists and chairside orthodontic assistants needed in Trinidad and Tobago. RESULTS: On average, 50 per cent of the 289 patients treated by each orthodontist in Trinidad and Tobago annually are children. Approximately, 13 360 patients can be expected to demand orthodontic treatment every year in this country. The number of orthodontists and chairside assistants required to treat these patients was estimated to be 44 and 154, respectively. CONCLUSIONS: Currently, Trinidad and Tobago only has a quarter of the number of orthodontists and orthodontic chairside assistants required to treat the number of patients in need. As the demand is relatively high in Trinidad and Tobago and the number of orthodontists has increased slowly and inadequately for the past decade, the orthodontists are likely to remain adequately employed and happy with their job unlike dentists who are currently in private practice for less than a year.

Orthodontic treatment need of children in Trinidad and Tobago.

OBJECTIVE: This prospective cross-sectional study was undertaken to determine the normative and perceived orthodontic treatment needs of children aged 11-12 years in a Caribbean country, Trinidad and Tobago. METHODS: One author, an experienced orthodontist, examined 367 children using the Dental Health Component (DHC) of the Index of Orthodontic Treatment Need (IOTN) to assess the normative need. The same orthodontist administered the questionnaire to assess the patient's perceived needs using the Aesthetic Component (AC) of the IOTN and the Oral Aesthetic Subjective Impact Scale (OASIS). RESULTS: The DHC and the AC of the IOTN and the OASIS showed respectively that 61.4%, 2.5% and 0.6% of the children had definite need for orthodontic treatment. The female proportion of the sample was more than the target population but the perceived need and normative need for orthodontic treatment did not depend significantly (p < 0.05) on the gender or ethnicity of the subjects of this study. The perception of need for orthodontic treatment differed inversely from the normative need and this is seen to be significant (p < 0.05) when OASIS was used. CONCLUSIONS: Approximately three out of five children in Trinidad and Tobago have a great (or very great) need for orthodontic treatment for dental health reasons.

A qualitative assessment of the pulmonary rehabilitation decision-making needs of patients living with COPD.

Pulmonary rehabilitation (PR) is highly evidenced but underutilised in patients living with chronic obstructive pulmonary disease (COPD). A menu of centre and home-based programmes is available to facilitate uptake but is not routinely offered. An appraisal of the current PR referral approach compared to a menu-based approach was warranted to explore the decision-making needs of patients living with COPD when considering a referral to PR. Face-to-face or telephone, semi-structured interviews were conducted with patients diagnosed with COPD and referred to PR and referring HCPs. Interviews were audio-recorded, transcribed verbatim and analysed using the enhanced critical incident technique. 14 HCPs and 11 patients were interviewed (n = 25). Interview data generated 276 critical incidents which informed 28 categories (30 sub-categories). Five high-level themes captured patients' decision-making needs for PR: Understanding COPD, understanding PR, perceived ability to access PR, a desire to accept PR, and supporting the offer. A menu-based approach would further support patients' PR decision-making, however, insufficient knowledge of the programmes would limit its perceived feasibility and acceptability. The development of shared decision making interventions (e.g., a patient decision aid) to elicit patient-centred, meaningful discussions about the menu is suggested.

Short message service reminder intervention doubles sexually transmitted infection/HIV re-testing rates among men who have sex with men.

OBJECTIVES: To evaluate the impact of a short message service (SMS) reminder system on HIV/sexually transmitted infection (STI) re-testing rates among men who have sex with men (MSM). METHODS: The SMS reminder programme started in late 2008 at a large Australian sexual health clinic. SMS reminders were recommended 3-6 monthly for MSM considered high-risk based on self-reported sexual behaviour. The evaluation compared HIV negative MSM who had a HIV/STI test between 1 January and 31 August 2010 and received a SMS reminder (SMS group) with those tested in the same time period (comparison group) and pre-SMS period (pre-SMS group, 1 January 2008 and 31 August 2008) who did not receive the SMS. HIV/STI re-testing rates were measured within 9 months for each group. Baseline characteristics were compared between study groups and multivariate logistic regression used to assess the association between SMS and re-testing and control for any imbalances in the study groups. RESULTS: There were 714 HIV negative MSM in the SMS group, 1084 in the comparison group and 1753 in the pre-SMS group. In the SMS group, 64% were re-tested within 9 months compared to 30% in the comparison group (p<0.001) and 31% in the pre-SMS group (p<0.001). After adjusting for baseline differences, re-testing was 4.4 times more likely (95% CI 3.5 to 5.5) in the SMS group than the comparison group and 3.1 times more likely (95% CI 2.5 to 3.8) than the pre-SMS group. CONCLUSION: SMS reminders increased HIV/STI re-testing among HIV negative MSM. SMS offers a cheap, efficient system to increase HIV/STI re-testing in a busy clinical setting.

The development of evidence-informed physical activity guidelines for adults with spinal cord injury.

OBJECTIVES: To systematically develop evidence-informed physical activity guidelines to improve physical fitness in people with spinal cord injury (SCI). SETTING: This study was conducted in Canada. METHODS: The Appraisal of Guidelines, Research and Evaluation II guideline development protocol was used to develop exercise guidelines to improve physical capacity and muscular strength. The evidence base for the guideline development process consisted of a systematic review and quality appraisal of research examining the effects of exercise on physical fitness among people with SCI. A multidisciplinary expert panel deliberated the evidence and generated the guidelines. Pilot testing led to refinement of the wording and presentation of the guidelines. RESULTS: The expert panel generated the following guidelines: for important fitness benefits, adults with a SCI should engage in (a) at least 20 min of moderate to vigorous intensity aerobic activity two times per week and (b) strength training exercises two times per week, consisting of three sets of 8-10 repetitions of each exercise for each major muscle group. CONCLUSION: People with SCI, clinicians, researchers and fitness programmers are encouraged to adopt these rigorously developed guidelines.

Inhibition of antibiotic-resistant Staphylococcus aureus by the broad-spectrum dihydrofolate reductase inhibitor RAB1.

The bacterial burden on human health is quickly outweighing available therapeutics. Our long-term goal is the development of antimicrobials with the potential for broad-spectrum activity. We previously reported phthalazine-based inhibitors of dihydrofolate reductase (DHFR) with potent activity against Bacillus anthracis, a major component of Project BioShield. The most active molecule, named RAB1, performs well in vitro and, in a cocrystal structure, was found deep within the active site of B. anthracis DHFR. We have now examined the activity of RAB1 against a panel of bacteria relevant to human health and found broad-spectrum applicability, particularly with regard to gram-positive organisms. RAB1 was most effective against Staphylococcus aureus, including methicillin- and vancomycin-resistant (MRSA/VRSA) strains. We have determined the cocrystal structure of the wild-type and trimethoprim-resistant (Phe 98 Tyr) DHFR enzyme from S. aureus with RAB1, and we found that rotational freedom of the acryloyl linker region allows the phthalazine moiety to occupy two conformations. This freedom in placement also allows either enantiomer of RAB1 to bind to S. aureus, in contrast to the specificity of B. anthracis for the S-enantiomer. Additionally, one of the conformations of RAB1 defines a unique surface cavity that increases the strength of interaction with S. aureus. These observations provide insights into the binding capacity of S. aureus DHFR and highlight atypical features critical for future exploitation in drug development.

Follow-up of renal impairment results among attendees taking HIV Pre-Exposure Prophylaxis at a Sydney Sexual Health Clinic.

Renal monitoring is recommended for Pre-Exposure Prophylaxis (PrEP) users. We aimed to explore follow-up and outcomes among PrEP users with renal impairment (defined as estimated glomerular filtration rate <65 mL/min/1.73 m2) attending Sydney Sexual Health Centre. Time to follow-up was analysed for impairment results over a 12-month period (January-December 2018); 48/2504 (1.9%) tests among 1700 attendees showed impairment. Follow-up occurred in 39/48 (81.3%) impairment results after a median of 42 days. PrEP was ceased in 3/6 cases of non-resolving/persisting impairment, with one case of subsequent human immunodeficiency virus infection. Maintaining engagement and follow-up of those with renal impairment are important aspects of PrEP service provision.

Interrelated striated elements in vestibular hair cells of the rat.

Unusual fixation procedures revealed a series of interrelated striated organelles in type I and type II vestibular hair cells of the rat; these organelles seemed to be less well developed in cochlear hair cells. The findings suggest that contractile elements may play a role in sensory transduction in the inner ear, particularly in the vestibular system.

Improvements in sexual health testing among gay men in Sydney, Australia, 2003-2007.

In order to be effective, sexually transmitted infection (STI) testing should be comprehensive based on the clients' sexuality and risk practices. Using data from the Sydney Gay Community Periodic Survey, we explored trends in and factors associated with STI testing among gay men during 2003-2007. Among men who were not HIV-positive, 68% were tested for HIV in 2007. HIV testing was more common than STI testing and remained stable during 2003-2007. Use of swabs and urine samples increased significantly (P-trend<0.001 for each). However, until 2007, 33% of men were not tested. Sexual behaviours (higher number of partners, having casual partners and engaging in unprotected anal intercourse with them) were associated with STI testing. HIV-negative men were tested for STI less often than HIV-positive men (prevalence ratio=0.56; 95% CI: 0.47-0.68). STI testing among HIV-negative men has improved significantly but remains inadequate for STI control and HIV prevention. It should not be assumed that appropriate and comprehensive STI screening is always provided to clients.

Quality improvement program of adult urinary tract infection management: Review and impact.

OBJECTIVE: A quality improvement program for adult urinary tract infection management was established to avoid unnecessary antibiotic treatment and to promote adequate prescription, associated with financial and time savings. METHODS: Management was integrated into a three-step approach: clinical diagnosis, bacteriological diagnosis, and therapeutic decision. For each step, areas for improvement were prioritized and implemented through corrective measures and key messages, measured by indicators. This program was applied to the whole hospital, which includes an emergency department and hospital units (672 beds). RESULTS: The diffusion of new recommendations on clinical diagnosis helped limit the use of Urine Dipstick Tests (UDT) and identify situations requiring the prescription of urine cytobacteriological test (UCBE) and antibiotic treatment: decreased annual consumption of UDTs (34%) and UCBEs (25%). The implementation of a new sampling system for UCBEs was associated with a 21% increase in conclusive analysis. Results of antimicrobial susceptibility testing were also optimized. Trainings on the proper use of antibiotics led to a 5.0% decline in global consumption. Only 23 antibiotic prescriptions for UTI resulted in pharmaceutical advice to prescribers in 2014. CONCLUSION: The program is part of a practice improvement strategy. Integrating the management of urinary tract infections into a global process helped improve each step of patient management.

Dye binding probes of lipid-binding structures. An investigation of 2-p-toluidinylnaphthylene-6-sulfonate binding to human and bovine prothrombin and fragment 1 in the presence and absence of calcium and magnesium ions.

TNS (2-p-toluidinylnaphthylene-6-sulfonate) binds to human and bovine prothrombin and Fragment 1 in the absence and presence of added Ca2+. The stoichiometry of TNS binding is 1:1 for human and bovine prothrombin and Fragment 1. The Ca2+-dependence of the fluorescence of TNS bound to bovine prothrombin Fragment 1 yields a modified Hill plot slope of 2.7, which is consistent with the slope obtained by monitoring the Ca2+ dependence of protein fluorescence quenching, CD changes and phospholipid binding. Mg2+ has have no effect on the fluorescence of TNS-prothrombin fluorescence. TNS binding to the amino-terminal region of prothrombin is the first relatively simple probe of the subtle and complex relationship which exists between protein structure and phospholipid binding.

Clinical audit: adherence to sexually transmitted infection screening guidelines for men who have sex with men.

Australian guidelines recommend regular screening of men who have sex with men (MSM) for sexually transmitted infections (STIs). This audit was performed to determine STI testing rates in Sydney Sexual Health Centre before and after the development of the guidelines, and to describe characteristics of those not tested. The electronic clinic database and a manual file review were used to determine testing rates and reasons for not testing for the years 2000 and 2002. Overall testing rates were high, with 61% of MSM having had all recommended tests within the past year in 2002. There was a significant increase in testing rates for most tests after the development of the guidelines. Asymptomatic men were more likely to be tested than symptomatic men, and HIV-positive men were less likely to be tested for syphilis.

The comparative effectiveness of two digit-sucking deterrent methods.

A study was conducted to compare the effectiveness of the crib and positive reinforcement in eliminating anterior open bites and increased overjets caused by digit-sucking. The overjet and overbite were measured using an overjet ruler at the start and end of the seventeen-week observation period. Forty patients consented to participate but measurements were only obtained for 11 subjects. The trend in this study is that the crib is more effective than positive reinforcement in preventing digit-sucking.

Estrogenic triarylethylene acetic acids: effect of structural variation on estrogen receptor affinity and estrogenic potency and efficacy in MCF-7 cells.

Triarylethylenecarboxylic acids exemplified by (E,Z)-2-{4-[1-(p-hydroxyphenyl)-2-phenyl]-1-butenyl}phenoxyacetic acid (8) are a new class of estrogen receptor (ER) ligands capable of tissue selective estrogen agonist and antagonist effects. We report the syntheses of 8 and of analogues incorporating structural features known or anticipated to facilitate ER affinity in triarylethylenes. These studies revealed that the p-hydroxyphenyl moiety, ethylenic bond, and ether oxygen of 8 were all critical for high ER affinity. Although a 1,1-bisphenolic analogue bearing the p-(oxyacetic acid) moiety on its 2-phenyl ring, 12, had low ER affinity, it exhibited estrogenic potency approaching that of 8 in MCF-7 cells. Unlike 8 which was a partial agonist with weak antagonist potency, 12 was a full agonist. A similar profile of potency/efficacy in MCF-7 cells was seen in 9, an ethylenic bond saturated analogue of 8. Growth-promoting effects of 8, 9, and 12 were fully antagonized by the antiestrogen tamoxifen, suggesting that such effects were mediated solely via ER. Thus, our studies in MCF-7 cells have confirmed the estrogenicity of 8 and have enabled identification of two analogues with favorable estrogenic potency and full estrogen efficacy. On this basis, these three (triarylethylene)acetic acids have been selected for more intensive animal studies of their extrareproductive tract estrogenic effects.

A kinetic model describing the interaction of bovine prothrombin fragment 1 with calcium ions.

A kinetic model is derived for the interaction of bovine prothrombin fragment 1 with calcium ions. The model requires binding of a minimum of two calcium ions for induction of the observed biphasic fluorescence decrease as a function of time. The model is shown to be consistent with experimental kinetic and equilibrium data by fitting theoretical curves for the biphasic fluorescence change to the data through exact solution of the nonlinear differential rate equations derived from the model. The rate constants for the binding of these two required calcium ions are calculated from the solutions as best fit parameters. The thermodynamic equilibrium constants, K1 and K2, for the binding of these two calcium ions are calculated from ratios of the forward and reverse rate constants as 0.6 X 10(4) and 5.4 X 10(4), respectively. Thus, the model correctly predicts positively cooperative calcium ion binding for at least the two calcium ions required to induce fluorescence quenching.