ACTIVATION (PercutAneous Coronary inTervention prIor to transcatheter aortic VAlve implantaTION): A Randomized Clinical Trial.

OBJECTIVES: This study sought to determine if percutaneous coronary intervention (PCI) prior to transcatheter aortic valve replacement (TAVR) in patients with significant coronary artery disease would produce noninferior clinical results when compared with no PCI (control arm). BACKGROUND: PCI in patients undergoing TAVR is not without risk, and there are no randomized data to inform clinical practice. METHODS: Patients with severe symptomatic aortic stenosis and significant coronary artery disease with Canadian Cardiovascular Society class ≤2 angina were randomly assigned to receive PCI or no PCI prior to TAVR. The primary endpoint was a composite of all-cause death or rehospitalization at 1 year. Noninferiority testing (prespecified margin of 7.5%) was performed in the intention-to-treat population. RESULTS: At 17 centers, 235 patients underwent randomization. At 1 year, the primary composite endpoint occurred in 48 (41.5%) of the PCI arm and 47 (44.0%) of the no-PCI arm. The requirement for noninferiority was not met (difference: -2.5%; 1-sided upper 95% confidence limit: 8.5%; 1-sided noninferiority test P = 0.067). On analysis of the as-treated population, the difference was -3.7% (1-sided upper 95% confidence limit: 7.5%; P = 0.050). Mortality was 16 (13.4%) in the PCI arm and 14 (12.1%) in the no-PCI arm. At 1 year, there was no evidence of a difference in the rates of stroke, myocardial infarction, or acute kidney injury, with higher rates of any bleed in the PCI arm (P = 0.021). CONCLUSIONS: Observed rates of death and rehospitalization at 1 year were similar between PCI and no PCI prior to TAVR; however, the noninferiority margin was not met, and PCI resulted in a higher incidence of bleeding. (Assessing the Effects of Stenting in Significant Coronary Artery Disease Prior to Transcatheter Aortic Valve Implantation; ISRCTN75836930).

CLEAR - Contact lens optics.

The most fundamental aspect of a contact lens is its optics; the manner in which the refraction of light is managed to optimise vision to the clinical benefit of the lens wearer. This report presents contemporary information on the optical structure of the eye and the optical models employed to understand the correction of refractive error. The design, measurement and clinical assessment of spherical, aspheric, toric, multifocal and myopia control contact lenses are described. The complexity and variety of multifocal lenses is recognised and detailed information is provided for alternating, simultaneous, diffractive, annular, aspheric and extended depth of field lens designs. In terms of clinical assessment, a contemporary review is provided for the measurement of: visual acuity, contrast sensitivity, through focus curves, reading performance, peripheral refraction, toric displacement realignment and patient reported outcomes. Overall, the paper aims to serve as a resource for the prescribing clinician, who can optimise contact lens corrections for patients by building on the optical rationale of these devices; and also highlights future opportunities for research innovation.

Survival relative to pacemaker status after transcatheter aortic valve implantation.

OBJECTIVES: To determine whether a permanent pacemaker (PPM) in situ can enhance survival after transcatheter aortic valve implantation (TAVI), in a predominantly inoperable or high risk cohort. BACKGROUND: New conduction disturbances are the most frequent complication of TAVI, often necessitating PPM implantation before hospital discharge. METHODS: We performed an observational cohort analysis of the UK TAVI registry (2007-2015). Primary and secondary endpoints were 30-day post-discharge all-cause mortality and long-term survival, respectively. RESULTS: Of 8,651 procedures, 6,815 complete datasets were analyzed. A PPM at hospital discharge, irrespective of when implantation occurred (PPM 1.68% [22/1309] vs. no PPM 1.47% [81/5506], odds ratio [OR] 1.14, 95% confidence interval [CI] 0.71-1.84; p = .58), or a PPM implanted peri- or post-TAVI only (PPM 1.44% [11/763] vs. no PPM 1.47% [81/5506], OR 0.98 [0.51-1.85]; p = .95) did not significantly reduce the primary endpoint. Patients with a PPM at discharge were older, male, had right bundle branch block at baseline, were more likely to have received a first-generation self-expandable prosthesis and had experienced more peri- and post-procedural complications including bailout valve-in-valve rescue, bleeding and acute kidney injury. A Cox proportional hazards model demonstrated significantly reduced long-term survival in all those with a PPM, irrespective of implantation timing (hazard ratio [HR] 1.14 [1.02-1.26]; p = .019) and those receiving a PPM only at the time of TAVI (HR 1.15 [1.02-1.31]; p = .032). The reasons underlying this observation warrant further investigation. CONCLUSIONS: A PPM did not confer a survival advantage in the first 30 days after hospital discharge following TAVI.

In-hospital stroke after transcatheter aortic valve implantation: A UK observational cohort analysis.

OBJECTIVES: We sought to identify baseline demographics and procedural factors that might independently predict in-hospital stroke following transcatheter aortic valve implantation (TAVI). BACKGROUND: Stroke is a recognized, albeit infrequent, complication of TAVI. Established predictors of procedure-related in-hospital stroke; however, remain poorly defined. METHODS: We conducted an observational cohort analysis of the multicenter UK TAVI registry. The primary outcome measure was the incidence of in-hospital stroke. RESULTS: A total of 8,652 TAVI procedures were performed from 2007 to 2015. There were 205 in-hospital strokes reported by participating centers equivalent to an overall stroke incidence of 2.4%. Univariate analysis showed that the implantation of balloon-expandable valves caused significantly fewer strokes (balloon-expandable 96/4,613 [2.08%] vs. self-expandable 95/3,272 [2.90%]; p = .020). After multivariable analysis, prior cerebrovascular disease (CVD) (odds ratio [OR] 1.51, 95% confidence interval [CI 1.05-2.17]; p = .03), advanced age at time of operation (OR 1.02 [0.10-1.04]; p = .05), bailout coronary stenting (OR 5.94 [2.03-17.39]; p = .008), and earlier year of procedure (OR 0.93 [0.87-1.00]; p = .04) were associated with an increased in-hospital stroke risk. There was a reduced stroke risk in those who had prior cardiac surgery (OR 0.62 [0.41-0.93]; p = .01) and a first-generation balloon-expandable valve implanted (OR 0.72 [0.53-0.97]; p = .03). In-hospital stroke significantly increased 30-day (OR 5.22 [3.49-7.81]; p < .001) and 1-year mortality (OR 3.21 [2.15-4.78]; p < .001). CONCLUSIONS: In-hospital stroke after TAVI is associated with substantially increased early and late mortality. Factors independently associated with in-hospital stroke were previous CVD, advanced age, no prior cardiac surgery, and deployment of a predominantly first-generation self-expandable transcatheter heart valve.

Transcatheter aortic valve implantation via surgical subclavian versus direct aortic access: A United Kingdom analysis.

BACKGROUND: Surgical subclavian (SC) and direct aortic (DA) access are established alternatives to the default transfemoral route for transcatheter aortic valve implantation (TAVI). We sought to find differences in survival and procedure-related outcomes after SC- versus DA-TAVI. METHODS: We performed an observational cohort analysis of cases prospectively uploaded to the UK TAVI registry. To ensure the most contemporaneous comparison, the analysis focused on SC and DA procedures performed from 2013 to 2015. RESULTS: Between January 2013 and July 2015, 82 (37%) SC and 142 (63%) DA cases were performed that had validated 1-year life status. Multivariable regression analysis showed procedure duration was longer for SC cases (SC 193.5 ± 65.8 vs. DA 138.4 ± 57.7 min; p < .01) but length of hospital stay was shorter (SC 8.6 ± 9.5 vs. DA 11.9 ± 10.8 days; p = .03). Acute kidney injury was observed less frequently after SC cases (odds ratio [OR] 0.35, 95% confidence interval [CI 0.12-0.96]; p = .042) but vascular access site-related complications were more common (OR 9.75 [3.07-30.93]; p < .01). Procedure-related bleeding (OR 0.54 [0.24-1.25]; p = .15) and in-hospital stroke rate (SC 3.7% vs. DA 2.1%; p = .67) were similar. There were no significant differences in in-hospital (SC 2.4% vs. DA 4.9%; p = .49), 30-day (SC 2.4% vs. DA 4.2%; p = .71) or 1-year (SC 14.5% vs. DA 21.9%; p = .344) mortality. CONCLUSIONS: Surgical subclavian and direct aortic approaches can offer favourable outcomes in appropriate patients. Neither access modality conferred a survival advantage but there were significant differences in procedural metrics that might influence which approach is selected.

Effect of procedural refinement of transfemoral transcatheter aortic valve implantation on outcomes and costs: a single-centre retrospective study.

Objectives: To determine the effect of introducing several procedural refinements of transfemoral transcatheter aortic valve implantation (TAVI) on clinical outcomes and costs. Design: Retrospective analysis comparing two consecutive 1-year periods, before and after the introduction of procedural refinements. Setting: Tertiary hospital aortic valve programme. Participants: Consecutive patients undergoing transfemoral TAVI treated between April 2014 and August 2015 using the initial setup (n=70; control group) or between September 2015 and August 2016 after the introduction of procedural refinements (n=89). Interventions: Introduction of conscious sedation, percutaneous access and closure, omission of transoesophageal echocardiography during the procedure, and an early discharge procedure. Outcome measures: Procedural characteristics, complications and outcomes; length of stay in intensive care unit (ICU) and hospital; hospital-related direct costs associated with TAVI. Results: There were no statistically significant differences in the incidence of complications or mortality between the two groups. The mean length of stay in the ICU was significantly shorter in the procedural-refinement group compared with the control group (5.1 vs 57.2 hours, p<0.001), as was the mean length of hospital stay (4.7 vs 6.6 days, p<0.001). The total cost per TAVI procedure was significantly lower, by £3580, in the procedural-refinement group (p<0.001). This was largely driven by lower ICU costs. Conclusions: Among patients undergoing transfemoral TAVI, procedural refinement facilitated a shorter stay in ICU and earlier discharge from hospital and was cost saving compared with the previous setup.

Transapical valve-in-ring mitral valve implantation through the anterior mitral valve leaflet.

Transcatheter mitral valve implantation (TMVI) is a relatively novel intervention used to replace the mitral valve of individuals deemed too high risk or unsuitable for surgery. It is associated with a number of specific risks, including left ventricular outflow tract obstruction (LVOTO).  In this video tutorial we present the case of a 75-year-old man who was unable to undergo redo surgical repair and had a number of risk factors for LVOTO. To minimize these risks, we deployed the TMVI within the anterior mitral valve leaflet. The postoperative result was mild mitral valve regurgitation and no LVOTO.  The long-term outcome of this approach is yet to be determined but we believe this technique offers a novel method to manage a select group of patients suffering with mitral valve disease and at risk of LVOTO.

Transapical valve-in-ring mitral valve implantation through the anterior mitral valve leaflet.

Transcatheter mitral valve implantation is a relatively novel intervention that replaces the mitral valve of individuals deemed too high-risk or unsuitable for surgery. It is associated with a number of specific risks, including left ventricular outflow tract obstruction. In this report, we present the case of a 75-year-old man who was unable to undergo redo surgical repair and had a number of risk factors for left ventricular outflow tract obstruction. To minimize this risk, we deployed transcatheter mitral valve implantation within the anterior mitral valve leaflet resulting in mild mitral valve regurgitation postoperatively and no left ventricular outflow tract obstruction. Long-term durability of this approach is yet to be determined, but we believe that this intervention adds to the armamentarium of the heart team.

Optical Assessment of Soft Contact Lens Edge-Thickness.

PURPOSE: To assess the edge shape of soft contact lenses using Gabor-Domain Optical Coherence Microscopy (GD-OCM) with a 2-µm imaging resolution in three dimensions and to generate edge-thickness profiles at different distances from the edge tip of soft contact lenses. METHODS: A high-speed custom-designed GD-OCM system was used to produce 3D images of the edge of an experimental soft contact lens (Bausch + Lomb, Rochester, NY) in four different configurations: in air, submerged into water, submerged into saline with contrast agent, and placed onto the cornea of a porcine eyeball. An algorithm to compute the edge-thickness was developed and applied to cross-sectional images. The proposed algorithm includes the accurate detection of the interfaces between the lens and the environment, and the correction of the refraction error. RESULTS: The sharply defined edge tip of a soft contact lens was visualized in 3D. Results showed precise thickness measurement of the contact lens edge profile. Fifty cross-sectional image frames for each configuration were used to test the robustness of the algorithm in evaluating the edge-thickness at any distance from the edge tip. The precision of the measurements was less than 0.2 µm. CONCLUSIONS: The results confirmed the ability of GD-OCM to provide high-definition images of soft contact lens edges. As a nondestructive, precise, and fast metrology tool for soft contact lens measurement, the integration of GD-OCM in the design and manufacturing of contact lenses will be beneficial for further improvement in edge design and quality control. In the clinical perspective, the in vivo evaluation of the lens fitted onto the cornea will advance our understanding of how the edge interacts with the ocular surface. The latter will provide insights into the impact of long-term use of contact lenses on the visual performance.

Quantitative optical inspection of contact lenses immersed in wet cell using swept source OCT.

We demonstrate swept source optical coherence tomography (OCT) imaging of contact lenses (CLs) in a wet cell and comprehensive quantitative characterization of CLs from volumetric OCT datasets. The approach is based on a technique developed for lens autopositioning and autoleveling enabled by lateral capillary interactions between the wet cell wall and the lens floating on the liquid surface. The demonstrated OCT imaging has enhanced contrast due to the application of a scattering medium and it improves visualization of both CL interfaces and edges. We also present precise and accurate three-dimensional metrology of soft and rigid CLs based on the OCT data. The accuracy and precision of the extracted lens parameters are compared with the manufacturer's specifications. The presented methodology facilitates industrial inspection methods of the CLs.

Predicting through-focus visual acuity with the eye's natural aberrations.

PURPOSE: To develop a predictive optical modeling process that utilizes individual computer eye models along with a novel through-focus image quality metric. METHODS: Individual eye models were implemented in optical design software (Zemax, Bellevue, WA) based on evaluation of ocular aberrations, pupil diameter, visual acuity, and accommodative response of 90 subjects (180 eyes; 24-63 years of age). Monocular high-contrast minimum angle of resolution (logMAR) acuity was assessed at 6 m, 2 m, 1 m, 67 cm, 50 cm, 40 cm, 33 cm, 28 cm, and 25 cm. While the subject fixated on the lowest readable line of acuity, total ocular aberrations and pupil diameter were measured three times each using the Complete Ophthalmic Analysis System (COAS HD VR) at each distance. A subset of 64 mature presbyopic eyes was used to predict the clinical logMAR acuity performance of five novel multifocal contact lens designs. To validate predictability of the design process, designs were manufactured and tested clinically on a population of 24 mature presbyopes (having at least +1.50 D spectacle add at 40 cm). Seven object distances were used in the validation study (6 m, 2 m, 1 m, 67 cm, 50 cm, 40 cm, and 25 cm) to measure monocular high-contrast logMAR acuity. RESULTS: Baseline clinical through-focus logMAR was shown to correlate highly (R² = 0.85) with predicted logMAR from individual eye models. At all object distances, each of the five multifocal lenses showed less than one line difference, on average, between predicted and clinical normalized logMAR acuity. Correlation showed R² between 0.90 and 0.97 for all multifocal designs. CONCLUSIONS: Computer-based models that account for patient's aberrations, pupil diameter changes, and accommodative amplitude can be used to predict the performance of contact lens designs. With this high correlation (R² ≥ 0.90) and high level of predictability, more design options can be explored in the computer to optimize performance before a lens is manufactured and tested clinically.

Population spherical aberration: associations with ametropia, age, corneal curvature, and image quality.

PURPOSE: The aim of this analysis was to determine the total ocular wavefront aberration values of a large phakic population of physiologically normal, ametropic eyes, gathered under the same clinical protocol using the same diagnostic wavefront sensor. MATERIALS AND METHODS: Studies were conducted at multiple sites in Asia, North America, Europe, and Australia. A Bausch + Lomb Zywave II Wavefront Aberrometer (Rochester, NY, USA) was used to measure the lower and higher order aberrations of each eye. Data analysis was conducted using linear regression analysis to determine the relationship between total spherical aberration, ametropia, age, corneal curvature, and image quality. RESULTS: Linear regression analysis showed no correlation (r = 0.0207, P = 0.4874) between degree of ametropia and the amount of spherical aberration. There was also no correlation when the population was stratified into myopic and hyperopic refractive groups (r m = 0.0529, P m = 0.0804 and r h = 0.1572, P h = 0.2754). There was a statistically significant and weak positive correlation (r = 0.1962, P < 0.001) between age and the amount of spherical aberration measured in the eye; spherical aberration became more positive with increasing age. Also, there was a statistically significant and moderately positive correlation (r = 0.3611, P < 0.001) with steepness of corneal curvature; spherical aberration became more positive with increasing power of the anterior corneal surface. Assessment of image quality using optical design software (Zemax™, Bellevue, WA < USA) showed that there was an overall benefit in correcting the average spherical aberration of this population. CONCLUSION: Analysis of this dataset provides insights into the inherent spherical aberration of a typical phakic, pre-presbyopic, population and provides the ability to determine what drives the spherical aberration of the eye, as well as what potential benefit a person could gain by compensating for that average spherical aberration.

Tibial intraneural ganglia at the ankle and knee: incorporating the unified (articular) theory in adults and children.

OBJECT: The etiology of intraneural ganglia has been debated for centuries, and only recently a unifying theory has been proposed. The incidence of tibial nerve intraneural ganglia is restricted to the occasional case report, and there are no reported cases of these lesions in children. While evidence of the unifying theory for intraneural ganglia of the common peroneal nerve is strong, there are only a few reports describing the application of the theory in the tibial nerve. In this report the authors examine tibial nerve intraneural ganglia at the ankle and knee in an adult and a child, respectively, and describe the clinical utility of incorporating the unifying (articular) theory in the management of tibial intraneural ganglia in adults and children. METHODS: Cases of tibial intraneural ganglion cysts were examined clinically, radiologically, operatively, and histologically to demonstrate the application of the unified (articular) theory for the development of these cysts in adults and children. RESULTS: Two patients with intraneural ganglion cysts of the tibial nerve were identified: an adult with an intraneural ganglion cyst of the tibial nerve at the tarsal tunnel and a child with an intraneural ganglion cyst of the tibial nerve at the knee. In each case, preoperative MR imaging demonstrated the intraneural cyst and its connection to the adjacent joint via the articular branch to the subtalar joint and superior tibiofibular joint. At surgery the articular branch was identified and resected, thus disconnecting the tibial nerve intraneural cyst from the joint of origin. CONCLUSIONS: These cases detail the important features of intraneural ganglion cysts of the tibial nerve and document the clinical utility of incorporating the unifying (articular) theory for the surgical management of tibial intraneural ganglia in adults and children.

Efficacy of an aspheric treatment algorithm in decreasing induced spherical aberration after laser in situ keratomileusis.

PURPOSE: To determine the effectiveness of an aspheric laser in situ keratomileusis (LASIK) algorithm for myopia with and without astigmatism in minimizing postoperative induction of spherical aberration. SETTING: Four sites in Asia. METHODS: Patients with -1.00 to -10.00 diopters (D) of spherical myopia with -4.00 D or less of astigmatism were recruited. Patients randomly had bilateral Zyoptix aspheric algorithm (aspheric group) or bilateral conventional Zyoptix Tissue Saving algorithm (control group). A Technolas 217z100 excimer system was used for LASIK ablation. Visual effectiveness, safety, higher-order aberrations, and corneal asphericity (Q value) were evaluated postoperatively. RESULTS: The aspheric group comprised 86 eyes and the control group, 84 eyes. At 3 months, the high-contrast uncorrected distance visual acuity was 20/20 or better in 78% of eyes in the aspheric group and 83% of eyes in the control group. The control treatment induced 0.22 microm of spherical aberration, which was significantly higher than the 0.04 microm induced with the aspheric treatment (6.0 mm pupil) (P<.0001). The aspheric treatment induced significantly less vertical coma and trefoil (P = .02). Eyes in the aspheric group had significantly lower Q values (P<.0001). There was no statistically significant difference in the manifest refraction spherical equivalent between the 2 groups (P >.05). Although high- and low-contrast corrected distance visual acuity (CDVA) was similar between the groups, the aspheric group gained more lines of low-contrast CDVA. CONCLUSION: The aspheric algorithm was more effective than the conventional algorithm in reducing induced spherical aberration and maintaining corneal asphericity after myopic LASIK.

The influence of first near-spectacle reading correction on accommodation and its interaction with convergence.

PURPOSE: Accommodation and convergence can adapt to blur and disparity stimuli and to age-related changes in accommodative amplitude. Does this ability decline with age? The authors investigated short-term adaptation to first near-spectacle reading correction on the accommodative-stimulus response (ASR) function, accommodative amplitude (AA), AC/A, and CA/C ratios in a pre-presbyopic and an incipient presbyopic population and determined whether changes in these functions recovered after discontinuation of the use of near spectacles. METHODS: Thirty subjects with normal vision participated; their ages ranged from 21 to 30 years (n = 15) and 38 to 44 years (n = 15). Oculomotor functions were measured before and after single-vision reading spectacles were worn for near tasks over a 2-month period and then 2 months after the use of near spectacles was discontinued. RESULTS: The slope of the ASR function and the AC/A and CA/C ratios did not change significantly after near spectacles were worn. There was a hyperopic shift of the ASR function that significantly reduced the near point of accommodation (NPA) and lowered the far-point refraction. These changes were age invariant and did not recover after 2 months of discontinuation of near spectacle wear. CONCLUSIONS: These results imply that the NPA may be enhanced normally by tonic bias of accommodation that elevates the entire ASR function and produces myopic refraction bias. When this bias relaxes after reading spectacles are worn, there is a hyperopic shift of the refractive state and a reduction of the NPA, specified from optical infinity.

Upper and lower tear menisci on contact lenses.

PURPOSE: The purpose of this study was to measure upper and lower tear menisci on contact lenses using real time optical coherence tomography (OCT). METHODS: Both eyes of 20 adapted contact lens wearers were imaged when they wore two types of silicone hydrogel lenses, balafilcon A on one eye and galyfilcon A on the other eye. The height, radius, and area of upper and lower tear menisci were obtained before, immediately after, and 20 minutes after lens wear on two consecutive days. On a third visit, the lenses were switched between eyes and an investigative lubricant was instilled after 4 hours of lens wear. OCT images were obtained as before and additionally at 1 and 4 hours after lens insertion. Imaging was also conducted immediately after lubricant instillation and 20 minutes post-instillation. RESULTS: There were no significant differences in the measured variables between lenses (P > 0.05) and between consecutive visits (P > 0.05). The menisci around both eyelids immediately after lens insertion were significantly greater than that before (P < 0.005). By 20 minutes after lens insertion, all variables had returned to baseline values and remained that way for at least 4 hours. Immediately after the instillation of the lubricant at 4 hours, meniscus variables increased (P < 0.001), but recovery to baseline occurred within 20 minutes. CONCLUSIONS: It is feasible to use OCT in the measurement of both upper and lower tear menisci on contact lenses in situ. Tear menisci increased on insertion of contact lenses and on instillation of lubricants. However baseline values were re-established with 20 minutes.

Usefulness of 64-detector row computed tomography for evaluation of intracoronary stents in symptomatic patients with suspected in-stent restenosis.

To determine whether 64-slice multidetector computed tomographic coronary angiography (MDCTA) can accurately assess the coronary artery lumen in symptomatic patients with previous coronary artery stents and potential in-stent restenosis (ISR). The primary aim was to determine the accuracy of binary ISR exclusion using MDCTA compared with invasive catheter angiography (ICA). Secondary aims were comparisons of stent dimensions measured using MDCTA and variables that affect accuracy. Forty patients with previous stent placement underwent both ICA and 64-slice MDCTA after elective presentation with chest pain, and ICA quantitative coronary angiographic data were used as the reference standard. Thirty-six men and 4 women (age 64 +/- 10 years; range 44 to 83) with 103 stents (2.8 +/- 1.6 stents/patient) were comparatively evaluated (stent exclusion rate 9.6%). There were 45 bare-metal and 58 drug-eluting stents (20 +/- 18 months after implantation) with an average diameter of 3.23 +/- 0.7 mm. Overall accuracy for the detection of significant ISR showed sensitivity, specificity, and positive and negative predictive values of 85%, 86%, 61%, and 96% for proximal stents > or =3 mm, which improved to 100%, 94%, 81%, and 100%; if the visible luminal diameter on MDCTA was <1.5 mm, accuracy decreased to 40%, 84%, 29%, and 90%, respectively. In conclusion, 64-slice MDCTA assessment of symptomatic patients with suspected clinically significant ISR is a realistic alternative to ICA if reference stent diameter is > or =2.5 mm and visible lumen cross-sectional diameter is > or =1.5 mm, for which a negative MDCTA result virtually excludes the presence of significant ISR.