Summary of study A multi-country randomized, placebo-controlled trial of the safety, immunogenicity and efficacy of respiratory syncytial virus (RSV) F-protein nanoparticle vaccine was undertaken in 4,636 pregnant women and their infants. RSV F-protein vaccine was safe and immunogenic in the pregnant women inducing anti-F IgG, palivizumab-competing antibodies and RSV neutralizing antibodies that were transferred to the fetus. Although the primary endpoint of prevention of RSV-specific medically-significant lower respiratory tract infection (MS-LRTI) was not met per protocol criteria for efficacy (i.e. 97.52% lower bound >30%), vaccine efficacy was 39.4% (97.52% CI: -1.0, 63.7%; p=0.0278) in infants 0-90 days age. Furthermore, there was a 58.8% (95% CI 31.9, 75.0%) lower rate of RSV LRTI with severe hypoxemia (secondary endpoint) through to 90 days of age in the expanded intent-to-treat analysis. The number of women needed to be vaccinated to prevent RSV-specific MS-LRTI or LRTI with severe hypoxemia in their infants through to 180 days of life were 88 and 82, respectively. Background RSV is the dominant cause of severe lower respiratory tract infection (LRTI) in infants, with most severe disease concentrated in younger-age infants. Methods Healthy, pregnant women between 28 and 36 weeks gestation, with expected delivery near the start of the RSV season, were randomized to a single intramuscular dose of nanoparticle RSV F-protein vaccine, or placebo in a 2:1 ratio. Their infants were followed for 180 days for medically-significant LRTI (MS-LRTI), LRTI with severe hypoxemia and/or LRTI- hospitalization. RSV detection was performed centrally by PCR. Safety evaluation continued until 364 days age. Results 4,636 women were randomized, with 4,579 live births. Over the first 90 days of life, efficacy against RSV-MS-LRTI was 39.4% (97.52%CI: -1.0, 63.7%; p=0.0278) and 41.4% (95%CI: 5.3, 61.2%) in the per protocol and expanded intent-to-treat (eITT) analyses, respectively. There was a lower rate (efficacy 58.8%; 95%CI 31.9, 75.0% in eITT analysis; not adjusted for multiplicity) of RSV-LRTI with severe hypoxemia in infants of vaccinees through 90 days age. Pneumonia reported as a serious adverse events was 49.4% less common in infants of vaccinees (2.6%) than placebo-recipients through 364 days age. Conclusions Maternal vaccination with RSV F-nanoparticle vaccine was safe and immunogenic. The prespecified primary endpoint success criterion (efficacy 97.5% lower bound ≥30%) was not achieved. However, maternal immunization was associated with reduced risk of RSV-confirmed MS-LRTI and LRTI with severe hypoxemia in early infancy. Trial Registration Number ClinicalTrials.Gov: NCT02624947. Funding statement Funded by Novavax, with supporting grant from the Bill and Melinda Gates Foundation.

analysis demonstrates that the identified PAL-1 target genes affect specification, differentiation and morphogenesis of C-lineage cells. In particular, we show that cell fate-specific genes (or tissue identity genes) and a posterior HOX gene are activated in lineage-specific fashion. Transcription of targets is initiated in four temporal phases, which together with their spatial expression patterns leads to a model of the regulatory network specified by PAL-1.

PurposeTo investigate the vascular microcirculation changes in the retinal nerve fiber layer (RNFL) in normal, glaucoma suspect, and open-angle glaucoma (OAG) groups using optical coherence tomography–based microangiography (OMAG).MethodsOne eye from each subject was scanned with a Cirrus HD-OCT 5000–based OMAG prototype system montage scanning protocol centered at the optic nerve head (ONH). Blood flow signals were extracted using OMAG algorithm. Retinal nerve fiber layer vascular microcirculation was measured by calculating the blood flux index and vessel area density within a 1.2-mm width annulus centered at the ONH with exclusion of big retinal vessels. One-way ANOVA were performed to analyze the RNFL microcirculation among groups. Linear-regression models were constructed to analyze the correlation between RNFL microcirculation and clinical parameters. Discrimination capabilities of the flow metrics were assessed with the area under the receiver operating characteristic curve (AROC).ResultsTwenty normal, 26 glaucoma suspect, and 42 OAG subjects were enrolled. Eyes from OAG subjects and glaucoma suspects showed significantly lower blood flux index compared with normal eyes (P ≤ 0.0015). Retinal nerve fiber layer blood flow metrics showed significant correlations with visual field indices and structural changes in glaucomatous eyes (P ≤ 0.0123). Similar discrimination capability of blood flux index compared with RNFL thickness was found in both disease groups.ConclusionsPeripapillary RNFL vascular microcirculation measured as blood flux index by OMAG showed significant differences among OAG, glaucoma suspect, and normal controls and was significantly correlated with functional and structural defects. Retinal nerve fiber layer microcirculation measurement using OMAG may help physicians monitor glaucoma.

PurposeTo investigate optic disc perfusion differences in normal, primary open-angle glaucoma (POAG), and normal tension glaucoma (NTG) eyes using optical microangiography (OMAG) based optical coherence tomography (OCT) angiography technique.DesignCross-sectional, observational study.SubjectsTwenty-eight normal, 30 POAG, and 31 NTG subjects.MethodsOne eye from each subject was scanned with a 68 kHz Cirrus HD-OCT 5,000-based OMAG prototype system centered at the optic nerve head (ONH) (Carl Zeiss Meditec Inc, Dublin, CA). Microvascular images were generated from the OMAG dataset by detecting the differences in OCT signal between consecutive B-scans. The pre-laminar layer (preLC) was isolated by a semi-automatic segmentation program.Main Outcome MeasuresOptic disc perfusion, quantified as flux, vessel area density, and normalized flux (flux normalized by the vessel area) within the ONH.ResultsGlaucomatous eyes had significantly lower optic disc perfusion in preLC in all three perfusion metrics (p<0.0001) compared to normal eyes. The visual field (VF) mean deviation (MD) and pattern standard deviation (PSD) were similar between the POAG and NTG groups, and no differences in optic disc perfusion were observed between POAG and NTG. Univariate analysis revealed significant correlation between optic disc perfusion and VF MD, VF PSD, and rim area in both POAG and NTG groups (p≤0.0288). However, normalized optic disc perfusion was correlated with some structural measures (retinal nerve fiber layer thickness and ONH cup/disc ratio) only in POAG eyes.ConclusionsOptic disc perfusion detected with OMAG was significantly reduced in POAG and NTG groups compared to normal controls, but no difference was seen between POAG and NTG groups with similar levels of VF damage. Disc perfusion was significantly correlated with VF MD, VF PSD, and rim area in glaucomatous eyes. Vascular changes at the optic disc as measured using OMAG may provide useful information for diagnosis and monitoring of glaucoma.

To investigate the amount of bacterial dispersal associated with speech in a simulated intravitreous injection. Methods: Fifteen volunteers were recruited. Each volunteer was positioned over an open blood agar plate and did the following: read a 5-minute script with a face mask, read a 5-minute script without a face mask, read a 5-minute script with the face turned away from the plate without a face mask, and stood in silence for 5 minutes. Each volunteer then read a 5-minute script while reclined in a standard ophthalmic examination chair with an open blood agar plate secured to the forehead to simulate bacterial dispersal associated with a talking patient. Total numbers of colony-forming bacteria per plate were counted, and the bacteria were identified. Results: Significantly less bacterial growth occurred in the face mask and silence conditions compared with the no face mask condition (both PϽ.001). Bacterial growth was significantly greater in the reclined condition compared with the room control (P=.02). Oral streptococcal species represented 66.7% to 82.6% of bacterial colonies in the no face mask, face turned, and reclined conditions. Conclusions: During simulated intravitreous injection, wearing a face mask or remaining silent significantly decreases culture plate contamination from talking. Talking from above and talking in the reclined position were associated with a significant increase in culture plate contamination. Physicians performing intravitreous injections should be aware of these patterns of bacterial contamination, should consider either wearing a face mask or minimizing speech, and should encourage patients to minimize speech during the procedure.

Background Studies suggest obesity is associated with decreased prostate cancer risk. We hypothesized obesity is biologically associated with increased risk, though this is obscured due to hemodilution of PSA and larger prostate size. Methods Retrospective study of 441 consecutive men undergoing prostate biopsy between 1999 and 2003 at two equal access centers. The association between obesity (body mass index ≥30 kg/m2) and positive biopsy and Gleason ≥4+3 were estimated using logistic regression analysis adjusting for multiple clinical characteristics. Results 123 men (28%) were obese and 149 men (34%) had cancer. Median PSA and age were 5.7 ng/ml and 63.9 years. Obese men had significantly lower PSA concentrations (p=0.02) and larger prostate volumes (p=0.04). Obesity was not significantly related to age (p=0.19) or race (p=0.37). On univariate analysis, obesity was not associated with prostate cancer risk (OR 1.13, 95% CI 0.73–1.75, p=0.58). However, after adjusting for multiple clinical characteristics, obesity was associated with significantly increased prostate cancer risk (OR 1.98, 95% CI 1.17–3.32, p=0.01). After multivariable adjustment, there was no significant association between obesity and high-grade disease (p=0.18). Conclusions Without adjustment for clinical characteristics, obesity was not significantly associated with prostate cancer risk in this equal access clinic-based population. However, after adjusting for the lower PSA levels and the larger prostate size, obesity was associated with a 98% increased prostate cancer risk. These findings support the fact current prostate cancer screening practices may be biased against obese men.

IMPORTANCE Understanding the differences in vascular microcirculation of the peripapillary retinal nerve fiber layer (RNFL) between the hemispheres in eyes with glaucoma with single-hemifield visual field (VF) defects may provide insight into the pathophysiology of glaucoma.OBJECTIVE To investigate the changes in the microcirculation of the peripapillary RNFL of eyes with glaucoma by using optical microangiography. DESIGN, SETTING, AND PARTICIPANTSEyes with glaucoma and single-hemifield VF defect and normal eyes underwent scanning using an optical microangiography system covering a 6.7 × 6.7-mm 2 area centered at the optic nerve head. The RNFL microcirculation was measured within an annulus region centered at the optic nerve head divided into superior and inferior hemispheres. Blood flux index (the mean flow signal intensity in the vessels) and vessel area density (the percentage of the detected vessels in the annulus) were measured. MAIN OUTCOMES AND MEASURESDifferences in microcirculation between the hemispheres in eyes with glaucoma and normal eyes and correlations among blood flow metrics, VF thresholds, and clinical optical coherence tomography structural measurements were assessed.RESULTS Twenty-one eyes from 21 patients with glaucoma (7 men and 14 women; mean [SD] age, 63.7 [9.9] years) and 20 eyes from 20 healthy control individuals (9 men and 11 women; mean [SD] age, 68.3 [10.7] years) were studied. In eyes with glaucoma, the abnormal hemisphere showed a thinner RNFL (mean [SE] difference, 23.5 [4.5] μm; 95% CI, 15.1-32.0 μm; P < .001), lower RNFL blood flux index (mean [SE] difference, 0.04 [0.01]; 95% CI, 0.02-0.05; P < .001), and less vessel area density (mean [SE] difference, 0.08% [0.02%]; 95% CI, 0.05%-0.10%; P < .001) than did the normal hemisphere. Compared with normal eyes, reduced RNFL microcirculation was found in the normal hemisphere of eyes with glaucoma, measured by mean [SE] differences in blood flux index (0.06 [0.01]; 95% CI, 0.04-0.09; P < .001) and vessel area density (0.04% [0.02%]; 95% CI, 0.02%-0.08%; P = .003) but not in RNFL thickness (3.4 [4.7] μm; 95% CI, −6.2 to 12.9 μm; P = .48). Strong correlations were found between the blood flux index and VF mean deviation (Spearman ρ = 0.44; P = .045) and RNFL thickness (Spearman ρ = 0.65; P = .001) in the normal hemisphere of the eye with glaucoma.CONCLUSIONS AND RELEVANCE Reduced RNFL microcirculation was detected in the normal hemisphere of eyes with glaucoma, with strong correspondence with VF loss and RNFL thinning. Although the results suggest that vascular dysfunction precedes structural changes seen in glaucoma, longitudinal studies would be needed to confirm this finding.

Glaucoma is a leading cause of blindness worldwide and results from damage to the optic nerve. Currently, intraocular pressure is the only treatable risk factor. Changes in aqueous outflow regulate pressure; regulation becomes abnormal in glaucoma. From inside the eye aqueous flows out through the trabecular meshwork into a venous sinus called Schlemm's canal, next into collector channels and finally returns to the episcleral vessels of the venous system. The location of aqueous outflow regulation is unknown. Ex vivo and in vivo studies implicate both pressure-dependent trabecular tissue motion and tissues distal to Schlemm's canal in regulation of aqueous outflow. Technologies have not previously been available to study these issues. New ex vivo imaging in human eyes identifies hinged flaps or leaflets at collector channel entrances using a high-resolution spectral domain optical coherence tomography (SD-OCT) platform. The hinged flaps open and close in synchrony with pressure-dependent trabecular meshwork motion. The SD-OCT platform images from the trabecular meshwork surface while experimentally changing transtrabecular pressure gradients. New in vivo imaging in human eyes uses a motion sensitive technology, phase-sensitive OCT to quantitate real-time pulse-dependent trabecular tissue motion as well as absence of such motion when aqueous access to the outflow system is blocked. The recent studies suggest that aqueous outflow regulation results from synchronous pressure-dependent motion involving a network of interconnected tissues including those distal to Schlemm's canal. The new imaging technologies may shed light on glaucoma mechanisms and provide guidance in the management of medical, laser and surgical decisions in glaucoma.