Primary Health Care (PHC) Search Filter: Bringing the evidence to shore

Surfing the internet for primary health care (PHC) literature produces waves of information that can lead a researcher to feel as though they are drowning in papers. Sifting through material to find the oysters containing pearls can be a complex task. With the PHC literature and evidence base rapidly increasing, Flinders Filters and the Primary Health Care Research & Information Service collaborated on a project to develop a search filter designed to facilitate easier access to this pool of PHC resources, by enabling efficient and effective retrieval of relevant literature. The PHC Search Filter was developed in the Ovid Medline platform with an extensive methodology comprising five phases including: constructing a gold standard set of PHC-specific articles; identifying relevant index terms and textwords; testing combinations of search terms; assessing the search strategy which performed most effectively; and translating the filter for use in PubMed to enable ‘one click searching’. This presentation will introduce the PHC Search Filter, addressing its development and showcasing the tool through an audiovisual ‘how to’ segment. In addition, the presentation will report on a mixed-methods study used to evaluate the Filter, four months after its launch. This evaluation involved extensive advertising of an online survey with individuals invited to participate regardless of whether they had used the Filter or not. With 90 respondents, the survey provided details about the overarching benefits and positive response to the tool, and directions for further refinement of the Filter. The key findings from the evaluation noted that the PHC Search Filter reduces the burden associated with literature searching, increases the value of the results that are received, and provides a useful resource to improve the likelihood of incorporating evidence into policy and practice

Proteomic Analysis of Aortae from Human Lipoprotein(a) Transgenic Mice Shows an Early Metabolic Response Independent of Atherosclerosis

Background: Elevated low density lipoprotein (LDL) and lipoprotein(a) are independent risk factors for the development of atherosclerosis. Using a proteomic approach we aimed to determine early changes in arterial protein expression in transgenic mice containing both human LDL and lipoprotein(a) in circulation. Methods and Results: Plasma lipid analyses showed the lipoprotein(a) transgenic mice had significantly higher lipid levels than wildtype, including a much increased LDL and high density lipoprotein (HDL) cholesterol. Analysis of aortae from lipoprotein(a) mice showed lipoprotein(a) accumulation but no lipid accumulation or foam cells, leaving the arteries essentially atherosclerosis free. Using two-dimensional gel electrophoresis and mass spectrometry, we identified 34 arterial proteins with significantly altered abundance (P,0.05) in lipoprotein(a) transgenic mice compared to wildtype including 17 that showed a $2 fold difference. Some proteins of interest showed a similarly altered abundance at the transcript level. These changes collectively indicated an initial metabolic response that included a down regulation in energy, redox and lipid metabolism proteins and changes in structural proteins at a stage when atherosclerosis had not yet developed. Conclusions: Our study shows that human LDL and lipoprotein(a) promote changes in the expression of a unique set o

Switching antipsychotic medication to reduce sexual dysfunction in people with psychosis: the REMEDY RCT

BackgroundSexual dysfunction is common among people who are prescribed antipsychotic medication for psychosis. Sexual dysfunction can impair quality of life and reduce treatment adherence. Switching antipsychotic medication may help, but the clinical effectiveness and cost-effectiveness of this approach is unclear.ObjectiveTo examine whether or not switching antipsychotic medication provides a clinically effective and cost-effective method to reduce sexual dysfunction in people with psychosis.DesignA two-arm, researcher-blind, pilot randomised trial with a parallel qualitative study and an internal pilot phase. Study participants were randomised to enhanced standard care plus a switch of antipsychotic medication or enhanced standard care alone in a 1?:?1 ratio. Randomisation was via an independent and remote web-based service using dynamic adaptive allocation, stratified by age, gender, Trust and relationship status.SettingNHS secondary care mental health services in England.ParticipantsPotential participants had to be aged ??18 years, have schizophrenia or related psychoses and experience sexual dysfunction associated with the use of antipsychotic medication. We recruited only people for whom reduction in medication dosage was ineffective or inappropriate. We excluded those who were acutely unwell, had had a change in antipsychotic medication in the last 6 weeks, were currently prescribed clozapine or whose sexual dysfunction was believed to be due to a coexisting physical or mental disorder.InterventionsSwitching to an equivalent dose of one of three antipsychotic medications that are considered to have a relatively low propensity for sexual side effects (i.e. quetiapine, aripiprazole or olanzapine). All participants were offered brief psychoeducation and support to discuss their sexual health and functioning.Main outcome measuresThe primary outcome was patient-reported sexual dysfunction, measured using the Arizona Sexual Experience Scale. Secondary outcomes were researcher-rated sexual functioning, mental health, side effects of medication, health-related quality of life and service utilisation. Outcomes were assessed 3 and 6 months after randomisation. Qualitative data were collected from a purposive sample of patients and clinicians to explore barriers to recruitment.Sample sizeAllowing for a 20% loss to follow-up, we needed to recruit 216 participants to have 90% power to detect a 3-point difference in total Arizona Sexual Experience Scale score (standard deviation 6.0 points) using a 0.05 significance level.ResultsThe internal pilot was discontinued after 12 months because of low recruitment. Ninety-eight patients were referred to the study between 1 July 2018 and 30 June 2019, of whom 10 were randomised. Eight (80%) participants were followed up 3 months later. Barriers to referral and recruitment included staff apprehensions about discussing side effects, reluctance among patients to switch medication and reticence of both staff and patients to talk about sex.LimitationsInsufficient numbers of participants were recruited to examine the study hypotheses.ConclusionsIt may not be possible to conduct a successful randomised trial of switching antipsychotic medication for sexual functioning in people with psychosis in the NHS at this time.Future workResearch examining the acceptability and effectiveness of adjuvant phosphodiesterase inhibitors should be considered.Trial registrationCurrent Controlled Trials ISRCTN12307891.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 44. See the NIHR Journals Library website for further project information

Placenta Imaging Workshop 2018 report:Multiscale and multimodal approaches

The Centre for Medical Image Computing (CMIC) at University College London (UCL) hosted a two-day workshop on placenta imaging on April 12th and 13th 2018. The workshop consisted of 10 invited talks, 3 contributed talks, a poster session, a public interaction session and a panel discussion about the future direction of placental imaging. With approximately 50 placental researchers in attendance, the workshop was a platform for engineers, clinicians and medical experts in the field to network and exchange ideas. Attendees had the chance to explore over 20 posters with subjects ranging from the movement of blood within the placenta to the efficient segmentation of fetal MRI using deep learning tools. UCL public engagement specialists also presented a poster, encouraging attendees to learn more about how to engage patients and the public with their research, creating spaces for mutual learning and dialogue

Rates and Styles of Late Quaternary Deformation on the Wairarapa Fault, North Island, New Zealand

The Wairarapa Fault is a major active dextral strike-slip fault in the southern North Island of New Zealand. It is expressed at the surface as a highly segmented fault trace that occurs ~100-400 m east of the Tararua and Rimutaka Range front, where it cuts Last Glacial Maximum (LGM) aggradation gravels. Along its central section, northeast of the Waiohine River, the Wairarapa Fault progressively displaces a flight of post-LGM degradation terraces incised into the "Waiohine" surface at the top of these gravels. Detailed mapping of the variably displaced fluvial terraces at Waiohine River using a Real-Time Kinematic (RTK) Global Positioning System (GPS) and an Electronic Distance Meter (EDM) was used to produce Digital Elevation Models (DEM) from which, the displacements of terraces, risers and paleochannels could be quantified. The timing of fluvial terrace abandonment by the Waiohine River was constrained from previously published and newly obtained Optically Stimulated Luminescence (OSL) dating of post-abandonment sands and silts that mantle the Waiohine terraces. The cumulative dextral displacements of terrace risers range from 12.4 +/- 0.8 m (2 sigma) for the youngest terrace, to 101.1 +/- 3.4 m (2 sigma) for the oldest terrace (this is the Waiohine aggradation surface). The corresponding cumulative vertical displacements of the treads of these terraces range from 1.3 +/- 0.02 m (2 sigma) to 19.7 +/- 0.09 m (2 sigma). The ratio of horizontal to vertical slip for the seven Waiohine terraces averages 6.9 +/- 3.5 (2 sigma). A comparison between the paleochannel and adjacent riser displacements at the Waiohine terraces suggests that a complete riser trimming model for progressive fault displacements of flights of degradation terraces is most appropriate at this site. Under a complete trimming model, a riser begins recording displacement only after its lower bounding terrace tread is abandoned. We estimate the Late Quaternary dextral slip rate for the central part of the Wairarapa Fault by measuring the lateral offsets and abandonment ages of two terrace-riser pairs. Based on previously published OSL age data, and our new estimated displacement for the Waiohine aggradation surface, we calculate a dextral slip rate of 12.0 +/- 3.5 mm/yr (1 sigma) for the central Wairarapa Fault. The dextral displacement and maximum OSL age determined in this study for the next younger terrace require a minimum dextral slip rate of 7.2 +/- 0.8 mm/yr (1 sigma). We also determine the magnitudes of the inferred 1855 (smallest displacement) and penultimate (next-smallest displacement) single-event displacements at Waiohine terraces, as 12.4 +/- 0.8 m (2 sigma) and 9.7 +/- 1.7 m (2 sigma), respectively, implying a mean co-seismic dextral displacement of 10.6 +/- 2.6 m (2 sigma) at the Waiohine River for the last two earthquakes on the Wairarapa Fault. Previous studies suggest a northward decrease in slip rate, but are inconclusive as to the mechanism by which this decrease is accommodated. By comparing our slip rate and single-event displacement data with results from elsewhere along the fault, we infer that there has been a northward decrease in both long-term dextral slip rate and the mean size of co-seismic dextral displacements. Co-seismic dextral displacements are 10-30 % lower at Waiohine River than on the southern Wairarapa Fault (alongstrike distance of 15-20 km), and 10-50 % lower on the northern section of the fault near Mauriceville than at Waiohine River (along-strike distance of ~35 km). The decrease in Late Quaternary dextral slip rate northwards along the fault is therefore, probably a longer-term expression of such an along-strike reduction in the mean size of co-seismic strike-slip on Wairarapa Fault ruptures. This reduction may have been caused by a slip transfer off of the main fault and onto some combination of the Carterton, Masterton and Mokonui Faults, that splay northeast-ward off of that fault. The surface trace of the central section of the Wairarapa Fault is characterised by a series of left-stepping en echelon fault segments, where deformational pressure bulges have formed in the area of overlap between adjacent discontinuous strands. We mapped the fault and associated deformational surface features through a combination of field mapping and aerial photograph surveys. In addition, we used an RTK GPS to collect detailed topographic data across two particularly well defined pressure bulges, just south of the Waiohine River. Using this quantitative topographic data, we calculated the volumes of these two bulges, and the depths at which the faults bounding these bulges converge into a single fault plane. The near-surface 3D geometry of the Wairarapa Fault is defined by a three-order hierarchy of faults, where the lower two orders of faults are arranged in an en echelon array with respect to the next higher order fault. We define the first-order fault to be the single, northwest-dipping Wairarapa Fault plane that we infer to exist at depth within basement rock. The second-order (Type A) fault segments are defined to be 2-7 km long and separated by stepover widths of 250-350 m. These stepovers are where the largest (Type A) bulges have formed. Our volumetrically calculated fault convergence depth for Type A bulges are ~100-260 m, suggesting that Type A faults converge into a single Wairarapa Fault plane within basement rock, and well below the LGM Waiohine gravels. We infer that the Type A faults and bulges began forming within basement rock prior to Waiohine gravel deposition. The distinctly smaller, third-order (Type B) fault segments are 500-4000 m long and separated by fault stepover widths of 30-150 m. Between these segments, the smaller (Type B) bulges have formed. Our volumetrically calculated fault convergence depths for Type B faults are ~1-18 m, suggesting that the bulges bounding faults converge downwards at or near the base of the Waiohine gravels. The Type B bulges, therefore appear to have formed by distributed deformation of the near-surface Waiohine gravels after they had buried the pre-existing Wairarapa Fault plane in basement. The currently active Wairarapa Fault, located 100-400 m east of the range-front, we infer to be a relatively immature splay that has recently propagated upward through previously unfaulted material from an older Wairarapa Fault at depth, reflecting eastward propagation of deformation into the Wairarapa Valley in response to topographic loading of the Tararua and Rimutaka Ranges. The segmented, discontinuous characteristics of its surface fault zone suggest that the current fault strand is at an early stage of its evolution even at depth in basement, an apparent immaturity that is not simply restricted to the deformation of the surficial Waiohine gravels (e.g. Type B bulges). By reference to the results of previously published analogue models and up-scaling of these results to the dimensions of the natural setting, we qualitatively estimate a finite dextral displacement on the currently active strand of the Wairarapa Fault of between ~130 m and ~1700 m. Together with our new Late Quaternary dextral slip rate estimate for the central Wairarapa Fault, this would seem to imply an age of inception the currently active splay of the Wairarapa Fault in the Wairarapa Valley of perhaps 100-250 ka or younger. In the natural case of the Wairarapa Fault, en echelon fault segments ("R-faults") strike only 2 [degrees]-18 [degrees] (average of ~6-7 [degrees]) with respect to the average strike of the main fault in basement. This angle is much smaller than is modelled in analogue experiments of the deformation of a previously unfaulted overburden above a strikeslip to slightly oblique-slip basement fault (10 [degrees] -30 [degrees]). The width of the fault zone is also much narrower (350 m) for the Wairarapa Fault, than the scaled-up widths of the fault zones produced in these analogue models (1-2 km). These differences are interpreted to reflect the shallow fault convergence depths for the Wairarapa Fault in comparison to those created in the analogue models, which include a thick surficial "overburden" of unfaulted sand. That thick overburden allows the fault at depth to propagate upward as a wide splay-bounded fault zone at the surface. The surface structures along the Wairarapa Fault exhibit a strong plan-view asymmetry that is reflected in the consistently triangular shape of Type A and B pressure bulges and the across-strike asymmetry defined by the geometry of the faults and bulges in profile. Moreover, there is a partitioning of oblique slip components between the two different splays bounding a given pressure bulge along the Wairarapa Fault, where the northwest bounding fault strands exhibit a greater proportion of strikeslip displacement, and the southeast bounding faults exhibit a greater proportion of dip-slip displacement. This asymmetry is interpreted to be a result of the obliquity of convergence and the northwest dip of the master Wairarapa Fault plane at depth

Comparison of aorta lipids in wildtype and Lp(a) mice.

<p>A, Total cholesterol (TC), triglyceride (TG) and phospholipids (PL) in homogenized aorta lipid extracts (n = 6). TC and TG concentrations in the aorta of Lp(a) mice were significantly reduced compared to wildtype mice. B, Lp(a) mice had a significantly elevated concentration of thiobarbituric acid-reactive substances (TBARS) in the aorta compared to wildtype suggesting an accumulation of aldehydes from lipid oxidation. Data represented as mean concentration ± SEM.^**<i>P</i><0.01 versus wildtype.</p

RT-PCR analysis of transcripts of interest.

<p>Quantitative RT-PCR was performed to investigate if proteins of interest showing a ≥2 fold change at the protein level were also regulated at the mRNA transcript level between the Lp(a) and wildtype mice. Total RNA was isolated from aorta samples (n = 6) of wildtype and Lp(a) mice. RNA was reverse transcribed to cDNA and quantitative PCR for transcripts of interest relative to 18S rRNA was performed. Glucose-6-phosphate dehydrogenase (G6pdx) and peroxiredoxin 4 (Prdx4) transcripts were increased in Lp(a) mice compared to wildtype. Dihydrolipopoyllysine succinyltransferase (Dlst), Glycerol-3-phosphate dehydrogenase (Gpd1) and fatty acid-binding protein 4 (Fabp4) transcripts were decreased in Lp(a) mice compared to wildtype. Isocitrate dehydrogenase (Idh3a) transcript showed no significant difference in Lp(a) mice compared to wildtype mice. Results are presented as relative levels of transcript normalized to wildtype. ^***<i>P</i><0.001 versus wildtype.</p

Representative histological analysis of aortae from wildtype and Lp(a) mice.

<p>Aortic arches and sinuses of wildtype and Lp(a) mice (n = 8) were stained with haematoxylin and eosin (A and B) or Verhoeff's elastic stain and Curtis' modified van Gieson stain (C and D), which stained the elastic laminar (black), smooth muscle (brown), and collagen-rich fibrous tissue (red/pink). There was no evidence of atherosclerosis in the arteries of Lp(a) mice or wildtype mice, including no evidence of foam cells in the aortic arch or aortic sinus. Aortic arches were also immunostained with an anti-human Lp(a) antibody (brown) and counterstained with haematoxylin (blue). E, The wildtype mice were negative for Lp(a). F, The Lp(a) mice showed staining with the Lp(a)-specific antibody, indicating retention of Lp(a) in the arterial wall. Scale bar represents 100 µm.</p