Opioid-Sparing Effect of Cannabinoids: A Systematic Review and Meta-Analysis.

Cannabinoids, when co-administered with opioids, may enable reduced opioid doses without loss of analgesic efficacy (ie, an opioid-sparing effect). The aim of this study was to conduct a systematic review to determine the opioid-sparing potential of cannabinoids. Eligible studies included pre-clinical and clinical studies for which the outcome was either analgesia or opioid dose requirements. Clinical studies included controlled studies and case series. We searched Scopus, Cochrane Database of Systematic Reviews, Medline, and Embase. Nineteen pre-clinical and nine clinical studies met the search criteria. Seventeen of the 19 pre-clinical studies provided evidence of synergistic effects from opioid and cannabinoid co-administration. Our meta-analysis of pre-clinical studies indicated that the median effective dose (ED50) of morphine administered in combination with delta-9-tetrahydrocannabinol (delta-9-THC) is 3.6 times lower (95% confidence interval (CI) 1.95, 6.76; n=6) than the ED50 of morphine alone. In addition, the ED50 for codeine administered in combination with delta-9-THC was 9.5 times lower (95% CI 1.6, 57.5, n=2) than the ED50 of codeine alone. One case series (n=3) provided very-low-quality evidence of a reduction in opioid requirements with cannabinoid co-administration. Larger controlled clinical studies showed some clinical benefits of cannabinoids; however, opioid dose changes were rarely reported and mixed findings were observed for analgesia. In summary, pre-clinical studies provide robust evidence of the opioid-sparing effect of cannabinoids, whereas one of the nine clinical studies identified provided very-low-quality evidence of such an effect. Prospective high-quality-controlled clinical trials are required to determine the opioid-sparing effect of cannabinoids.

Linking the T cell receptor to the single cell transcriptome in antigen-specific human T cells.

Heterogeneity of T cells is a hallmark of a successful adaptive immune response, harnessing the vast diversity of antigen-specific T cells into a coordinated evolution of effector and memory outcomes. The T cell receptor (TCR) repertoire is highly diverse to account for the highly heterogeneous antigenic world. During the response to a virus multiple individual clones of antigen specific CD8+ (Ag-specific) T cells can be identified against a single epitope and multiple epitopes are recognised. Advances in single-cell technologies have provided the potential to study Ag-specific T cell heterogeneity at both surface phenotype and transcriptome levels, thereby allowing investigation of the diversity within the same apparent sub-population. We propose a new method (VDJPuzzle) to reconstruct the native TCRαß from single cell RNA-seq data of Ag-specific T cells and then to link these with the gene expression profile of individual cells. We applied this method using rare Ag-specific T cells isolated from peripheral blood of a subject who cleared hepatitis C virus infection. We successfully reconstructed productive TCRαß in 56 of a total of 63 cells (89%), with double α and double ß in 18, and 7% respectively, and double TCRαß in 2 cells. The method was validated via standard single cell PCR sequencing of the TCR. We demonstrate that single-cell transcriptome analysis can successfully distinguish Ag-specific T cell populations sorted directly from resting memory cells in peripheral blood and sorted after ex vivo stimulation. This approach allows a detailed analysis of the TCR diversity and its relationship with the transcriptional profile of different clones.

Intraocular Pressure Reduction Is Associated with Reduced Venous Pulsation Pressure.

PURPOSE: To explore whether alterations in intraocular pressure (IOP) affect vein pulsation properties using ophthalmodynamometric measures of vein pulsation pressure. PATIENTS AND METHODS: Glaucoma patients had two retinal vein pulsation pressure (VPP) measurements from upper and lower hemiveins performed by ophthalmodynamometry at least 3 months apart. All subjects had VPP and IOP recorded at two visits, with standard automated perimetry, central corneal thickness (CCT) recorded at the initial visit. Where venous pulsation was spontaneous ophthalmodynamometry could not be performed and VPP was considered equal to IOP. Change in VPP was calculated and binarized with reduction in pressure scored 1 and no change or increase scored as 0. Data analysis used a mixed logistic regression model with change in VPP as response variable and change in IOP, visual field loss (mean deviation), CCT and time interval as explanatory variables. RESULTS: 31 subjects (20 females) with mean age 60 years (sd 11) were examined with change in VPP being significantly associated with change in IOP (odds ratio 1.6/mmHg, 95% CI 1.2 to 2.1 in the glaucoma patients but not suspect patients (p = 0.0005). CONCLUSION: Change in VPP is strongly associated with change in IOP such that a reduced intraocular pressure is associated with a subsequent reduction in VPP. This indicates that reduced IOP alters some retinal vein properties however the nature and time course of these changes is not known.

Photoplethysmographic measurement of various retinal vascular pulsation parameters and measurement of the venous phase delay.

PURPOSE: Retinal vein pulsation properties are altered by glaucoma, intracranial pressure (ICP) changes, and retinal venous occlusion, but measurements are limited to threshold measures or manual observation from video frames. We developed an objective retinal vessel pulsation measurement technique, assessed its repeatability, and used it to determine the phase relations between retinal arteries and veins. METHODS: Twenty-three eyes of 20 glaucoma patients had video photograph recordings from their optic nerve and peripapillary retina. A modified photoplethysmographic system using video recordings taken through an ophthalmodynamometer and timed to the cardiac cycle was used. Aligned video frames of vessel segments were analyzed for blood column light absorbance, and waveform analysis was applied. Coefficient of variation (COV) was calculated from data series using recordings taken within ±1 unit ophthalmodynamometric force of each other. The time in cardiac cycles and seconds of the peak (dilation) and trough (constriction) points of the retinal arterial and vein pulse waveforms were measured. RESULTS: Mean vein peak time COV was 3.4%, and arterial peak time COV was 4.4%. Lower vein peak occurred at 0.044 cardiac cycles (0.040 seconds) after the arterial peak (P = 0.0001), with upper vein peak an insignificant 0.019 cardiac cycles later. No difference in COV for any parameter was found between upper or lower hemiveins. Mean vein amplitude COV was 12.6%, and mean downslope COV was 17.7%. CONCLUSIONS: This technique demonstrates a small retinal venous phase lag behind arterial pulse. It is objective and applicable to any eye with clear ocular media and has moderate to high reproducibility. ( http://www.anzctr.org.au number, ACTRN12608000274370.).

Spatial modeling of visual field data for assessing glaucoma progression.

PURPOSE: In order to reduce noise and account for spatial correlation, we applied disease mapping techniques to visual field (VF) data. We compared our calculated rates of progression to other established techniques. METHODS: Conditional autoregressive (CAR) priors, weighted to account for physiologic correlations, were employed to describe spatial and spatiotemporal correlation over the VF. Our model is extended to account for several physiologic features, such as the nerve fibers serving adjacent loci on the VF not mapping to the adjacent optic disc regions, the presence of the blind spot, and large measurement fluctuation. The models were applied to VFs from 194 eyes and fitted within a Bayesian framework using Metropolis-Hastings algorithms. RESULTS: Our method (SPROG for Spatial PROGgression) showed progression in 42% of eyes. Using a clinical reference, our method had the best receiver operating characteristics compared with the point-wise linear regression methods. Because our model intrinsically accounts for the large variation of VF data, by adjusting for spatial correlation, the effects of outliers are minimized, and spurious trends are avoided. CONCLUSIONS: by using CAR priors, we have modeled the spatial correlation in the eye. combining this with physiologic information, we are able to provide a novel method for VF analysis. model diagnostics, sensitivity, and specificity show our model to be apparently superior to CURRENT POINT-wise linear regression methods. (http://www.anzctr.org.au number, ACTRN12608000274370.).