Abstract
Conventional antidepressants, such as SSRIs, are an effective treatment for many patients with depression. However, for a significant proportion of patients SSRIs either lack efficacy or are ...poorly tolerated. Even when SSRIs are effective in treating mood symptoms, there are often residual symptoms that are not well treated, including cognitive impairment and anhedonia. The development of novel treatment for depression is particularly challenging given the limited predictive validity of animal models. Human neurocognitive models of antidepressant action can help to bridge the translational gap and allow rapid investigation of novel compounds in healthy volunteers and people with depression. In this talk, using the 5-HT
4
receptor as an example of a novel target of interest, I will outline how these objective neurocognitive models can be used as a translational tool to understand antidepressant treatment mechanisms, guide treatment selection and test novel putative antidepressants early in development.
Disclosure of Interest
S. Murphy Grant / Research support from: Zogenix, UCB, Janssen, Consultant of: Zogenix, Sumitomo Danippon, Janssen, UCB, Speakers bureau of: Zogenix
Since the pioneering work of Elie Metchnikoff and the discovery of cellular immunity, the phagocytic clearance of cellular debris has been considered an integral component of resolving inflammation ...and restoring function of damaged and infected tissues. We now know that the phagocytic clearance of dying cells (efferocytosis), particularly by macrophages and other immune phagocytes, has profound consequences on innate and adaptive immune responses in inflamed tissues. These immunomodulatory effects result from an array of molecular signaling events between macrophages, dying cells, and other tissue-resident cells. In recent years, many of these molecular pathways have been identified and studied in the context of tissue inflammation, helping us better understand the relationship between efferocytosis and inflammation. We review specific types of efferocytosis-related signals that can impact macrophage immune responses and discuss their relevance to inflammation-related diseases.
Cup malposition is a common cause of impingement, limitation of ROM, acceleration of bearing wear, liner fracture, and instability in THA. Previous studies of the safe zone based on plain radiographs ...have limitations inherent to measuring angles from two-dimensional projections. The current study uses CT to measure component position in stable and unstable hips to assess the presence of a safe zone for cup position in THA.
(1) Does acetabular component orientation, when measured on CT, differ in stable components and those revised for recurrent instability? (2) Do CT data support historic safe zone definitions for component orientation in THA?
We identified 34 hips that had undergone revision of the acetabulum for recurrent instability that also had a CT scan of the pelvis between August 2003 and February 2017. We also identified 175 patients with stable hip replacements who also had a CT study for preoperative planning and intraoperative navigation of the contralateral side. For each CT study, one observer analyzed major factors including acetabular orientation, femoral anteversion, combined anteversion (the sum of femoral and anatomic anteversion), pelvic tilt, total offset difference, head diameter, age, sex, and body mass index. These measures were then compared among stable hips, hips with cup revision for anterior instability, and hips with cup revision for posterior instability. We used a clinically relevant measurement of operative anteversion and inclination as opposed to the historic use of radiographic anteversion and inclination. The percentage of unstable hips in the historic Lewinnek safe zone was calculated, and a new safe zone was proposed based on an area with no unstable hips.
Anteriorly unstable hips compared with stable hips had higher operative anteversion of the cup (44° ± 12° versus 31° ± 11°, respectively; mean difference, 13°; 95% confidence interval CI, 5°-21°; p = 0.003), tilt-adjusted operative anteversion of the cup (40° ± 6° versus 26° ± 10°, respectively; mean difference, 14°; 95% CI, 10°-18°; p < 0.001), and combined tilt-adjusted anteversion of the cup (64° ± 10° versus 54° ± 19°, respectively; mean difference, 10°; 95% CI, 1°-19°; p = 0.028). Posteriorly unstable hips compared with stable hips had lower operative anteversion of the cup (19° ± 15° versus 31° ± 11°, respectively; mean difference, -12°; 95% CI, -5° to -18°; p = 0.001), tilt-adjusted operative anteversion of the cup (19° ± 13° versus 26° ± 10°, respectively; mean difference, -8°; 95% CI, -14° to -2°; p = 0.014), pelvic tilt (0° ± 6° versus 4° ± 6°, respectively; mean difference, -4°; 95% CI, -7° to -1°; p = 0.007), and anatomic cup anteversion (25° ± 18° versus 34° ± 12°, respectively; mean difference, -9°; 95% CI, -1° to -17°; p = 0.033). Thirty-two percent of the unstable hips were located in the Lewinnek safe zone (11 of 34; 10 posterior dislocations, one anterior dislocation). In addition, a safe zone with no unstable hips was identified within 43° ± 12° of operative inclination and 31° ± 8° of tilt-adjusted operative anteversion.
The current study supports the notion of a safe zone for acetabular component orientation based on CT. However, the results demonstrate that the historic Lewinnek safe zone is not a reliable predictor of future stability. Analysis of tilt-adjusted operative anteversion and operative inclination demonstrates a new safe zone where no hips were revised for recurrent instability that is narrower for tilt-adjusted operative anteversion than for operative inclination. Tilt-adjusted operative anteversion is significantly different between stable and unstable hips, and surgeons should therefore prioritize assessment of preoperative pelvic tilt and accurate placement in operative anteversion. With improvements in patient-specific cup orientation goals and acetabular component placement, further refinement of a safe zone with CT data may reduce the incidence of cup malposition and its associated complications.
Level III, diagnostic study.
Flavonoids are polyphenolic compounds found in all vascular and non-vascular plants. Although nonessential for plant growth and development, flavonoids have species-specific roles in nodulation, ...fertility, defense and UV protection. Flavonoids have been shown to modulate transport of the phytohormone auxin in addition to auxin-dependent tropic responses. However, flavonoids are not essential regulators of these processes because transport and tropic responses occur in their absence. Flavonoids modulate the activity of auxin-transporting P-glycoproteins and seem to modulate the activity of regulatory proteins such as phosphatases and kinases. Phylogenetic analysis suggests that auxin transport mechanisms evolved in the presence of flavonoid compounds produced for the scavenging of reactive oxygen species and defense from herbivores and pathogens.
Data are limited on the ability of dipyridamole to additionally inhibit platelet function/reactivity in ischaemic cerebrovascular disease (CVD) patients on aspirin.
To assess inhibition of platelet ...function/reactivity and platelet activation with dipyridamole in CVD.
This prospective, observational study assessed TIA/ischaemic stroke patients before (baseline; N = 60), at 14 ±7 days (14d, N = 39) and ≥ 90 days (90d, N = 31) after adding dipyridamole to aspirin. Platelet function/reactivity at high shear stress (PFA-100® C-ADP) and low shear stress (VerifyNow® P2Y12 and Multiplate® ADP assays), and platelet activation status (% expression of CD62P, CD63 and leucocyte-platelet complexes on whole blood flow cytometry) were quantified. ‘Dipyridamole-high on-treatment platelet reactivity (HTPR)’ was defined as failure to inhibit ADP-induced platelet aggregation +/- adhesion compared with the patient's baseline on aspirin monotherapy by more than twice the coefficient-of-variation of the assay after adding dipyridamole to aspirin.
Dipyridamole-HTPR was identified in 71.4–75% of patients on PFA-100 C-ADP, 83.9–86.8% of patients on VerifyNow P2Y12, and 81.5–83.3% of patients on Multiplate ADP assays. There were no changes in CD62P/CD63 expression (P ≥ 0.18), or consistent changes in leucocyte-platelet complexes in CVD patients overall at 14d or 90d vs. baseline after commencing dipyridamole. Monocyte-platelet complexes increased in the patient subgroup with dipyridamole-HTPR at 14d and 90d on PFA-100, and at 14d on VerifyNow (P ≤ 0.04), but not in those without dipyridamole-HTPR.
Additional antiplatelet effects of dipyridamole are detectable under high and low shear stress conditions with user-friendly platelet function/reactivity tests ex vivo. Increasing circulating monocyte-platelet complexes over time are associated with dipyridamole-HTPR.
The use of extracorporeal membrane oxygenation (ECMO) in critical care is gathering momentum internationally. There is interest in it being included within the offering of critical care services in ...South African (SA) state hospitals. Most discussions about ECMO’s appropriateness in state hospitals have focused on healthcare economics and cost: benefit ratio. To date, the bioethical considerations of this topic have not been comprehensively addressed. The present research aims to articulate some of the normative ethical considerations when making decisions about government funding of medical therapies in general, and costly life-sustaining treatments such as ECMO specifically, within a resource-limited environment. We used a standard normative/philosophical design and applied the ethical theories of responsive communitarianism and ubuntu (African moral theory) to investigate whether it is morally justifiable for intensive care units in SA state hospitals to be implementing ECMO programmes at present. We concluded that both responsive communitarianism and ubuntu advocate that when considering expensive therapies that extend or save lives, such as ECMO, it is essential to consider the collective effect of such treatments on the community – the benefits as well as burdens. Accordingly, considering the National Department of Health’s current state, it is ethically unjustified for ECMO to be included in the current critical care service in state hospitals at present.
SUMMARY
As an alternative to spectral methods, stochastic self-similar slip can be produced through a composite source model by placing a power-law scaling size-frequency distribution of circular ...slip dislocations on a fault surface. However these models do not accurately account for observed surface rupture behaviour. We propose a modification to the composite source model that corrects this issue. The advantage of this technique is that it accommodates the use of fractal slip distributions on non-planar fault surfaces. However to mimic a surface rupture using this technique, releasing the boundary condition at the top of the fault, we observed a systematic decrease in slip at shallow depths. We propose a new strategy whereby the surface is treated like a reflector with the slip being folded back onto the fault. Two different techniques based on this principal are presented: the first is the method of images. It requires a small change to pre-existing codes and works for planar faults. The second involves the use of a multistage trilateration technique. It is applied to non-planar faults described by an unstructured mesh. The reflected slip calculated using the two techniques is near identical on a planar fault, suggesting they are equivalent. Applying this correction, where reflected slip is accounted for in the composite source model, the lack of slip at shallow depths is not observed any more and there is no systematic trend with depth. However, there are other parameters which may affect the spatial distribution of slip across the fault plane. For example, the type of probability density function used in the placement of the subevent is also important. In the case where the location of maximum slip is known to a first order, a Gaussian may be appropriate to describe the probability function. For hazard assessment studies a uniform probability density function is more suitable as it provides no underlying systematic spatial trend.
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