Who are vaccine champions and what implementation strategies do they use to improve adolescent HPV vaccination? Findings from a national survey of primary care professionals.

BACKGROUND: Implementation science researchers often cite clinical champions as critical to overcoming organizational resistance and other barriers to the implementation of evidence-based health services, yet relatively little is known about who champions are or how they effect change. To inform future efforts to identify and engage champions to support HPV vaccination, we sought to describe the key characteristics and strategies of vaccine champions working in adolescent primary care. METHODS: In 2022, we conducted a national survey with a web-based panel of 2527 primary care professionals (PCPs) with a role in adolescent HPV vaccination (57% response rate). Our sample consisted of pediatricians (26%), family medicine physicians (22%), advanced practice providers (24%), and nursing staff (28%). Our survey assessed PCPs' experience with vaccine champions, defined as health care professionals "known for helping their colleagues improve vaccination rates." RESULTS: Overall, 85% of PCPs reported currently working with one or more vaccine champions. Among these 2144 PCPs, most identified the champion with whom they worked most closely as being a physician (40%) or nurse (40%). Almost all identified champions worked to improve vaccination rates for vaccines in general (45%) or HPV vaccine specifically (49%). PCPs commonly reported that champion implementation strategies included sharing information (79%), encouragement (62%), and vaccination data (59%) with colleagues, but less than half reported that champions led quality improvement projects (39%). Most PCPs perceived their closest champion as being moderately to extremely effective at improving vaccination rates (91%). PCPs who did versus did not work with champions more often recommended HPV vaccination at the earliest opportunity of ages 9-10 rather than later ages (44% vs. 33%, p < 0.001). CONCLUSIONS: Findings of our national study suggest that vaccine champions are common in adolescent primary care, but only a minority lead quality improvement projects. Interventionists seeking to identify champions to improve HPV vaccination rates can expect to find them among both physicians and nurses, but should be prepared to offer support to more fully engage them in implementing interventions.

Safety and immunogenicity of an HIV-1 prefusion-stabilized envelope trimer (Trimer 4571) vaccine in healthy adults: A first-in-human open-label, randomized, dose-escalation, phase 1 clinical trial.

Background: Advances in therapeutic drugs have increased life-expectancies for HIV-infected individuals, but the need for an effective vaccine remains. We assessed safety and immunogenicity of HIV-1 vaccine, Trimer 4571 (BG505 DS-SOSIP.664) adjuvanted with aluminum hydroxide (alum), in HIV-negative adults. Methods: We conducted a phase I, randomized, open-label, dose-escalation trial at the National Institutes of Health Clinical Center in Bethesda, MD, USA. Eligible participants were HIV-negative, healthy adults between 18-50 years. Participants were randomized 1:1 to receive Trimer 4571 adjuvanted with 500 mcg alum by either the subcutaneous (SC) or intramuscular (IM) route at weeks 0, 8, and 20 in escalating doses of 100 mcg or 500 mcg. The primary objectives were to evaluate the safety and tolerability of Trimer 4571 with a secondary objective of evaluating vaccine-induced antibody responses. The primary and safety endpoints were evaluated in all participants who received at least one dose of Trimer 4571. Trial results were summarized using descriptive statistics. This trial is registered at ClinicalTrials.gov, NCT03783130. Findings: Between March 7 and September 11, 2019, 16 HIV-negative participants were enrolled, including six (38%) males and ten (62%) females. All participants received three doses of Trimer 4571. Solicited reactogenicity was mild to moderate in severity, with one isolated instance of severe injection site redness (6%) following a third 500 mcg SC administration. The most commonly reported solicited symptoms included mild injection site tenderness in 14 (88%) and mild myalgia in six (38%) participants. The most frequent unsolicited adverse event attributed to vaccination was mild injection site pruritus in six (38%) participants. Vaccine-induced seropositivity occurred in seven (44%) participants and resolved in all but one (6%). No serious adverse events occurred. Trimer 4571-specific binding antibodies were detected in all groups two weeks after regimen completion, primarily focused on the glycan-free trimer base. Neutralizing antibody activity was limited to the 500 mcg dose groups. Interpretation: Trimer 4571 was safe, well tolerated, and immunogenic in this first-in-human trial. While this phase 1 trial is limited in size, our results inform and support further evaluation of prefusion-stabilized HIV-1 envelope trimers as a component of vaccine design strategies to generate broadly neutralizing antibodies against HIV-1. Funding: Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Biological effect on drug distribution and vascular healing via paclitaxel-coated balloon technology in drug eluting stent restenosis swine model.

OBJECTIVES: To evaluate the biological effect of a paclitaxel-coated balloon (PCB) technology on vascular drug distribution and healing in drug eluting stent restenosis (DES-ISR) swine model. BACKGROUND: The mechanism of action and healing response via PCB technology in DES-ISR is not completely understood. METHODS: A total of 27 bare metal stents were implanted in coronary arteries and 30 days later the in-stent restenosis was treated with PCB. Treated segments were harvested at 1 hr, 14 days and 30 days post treatment for the pharmacokinetic analysis. In addition, 24 DES were implanted in coronary arteries for 30 days, then all DES-ISRs were treated with either PCB (n = 12) or uncoated balloon (n = 12). At day 60, vessels were harvested for histology following angiography and optical coherence tomography (OCT). RESULTS: The paclitaxel level in neointimal tissue was about 18 times higher (P = 0.0004) at 1 hr Cmax , and retained about five times higher (P = 0.008) at day 60 than that in vessel wall. A homogenous distribution of paclitaxel in ISR was demonstrated by using fluorescently labeled paclitaxel. Notably, in DES-ISR, both termination OCT and quantitative coronary angioplasty showed a significant neointimal reduction and less late lumen loss (P = 0.05 and P = 0.03, respectively) post PCB versus post uncoated balloon. The PES-ISR + PCB group displayed higher levels of peri-strut inflammation and fibrin scores compared to the -limus DES-ISR + PCB group. CONCLUSIONS: In ISR, paclitaxel is primarily deposited in neointimal tissue and effectively retained over time following PCB use. Despite the presence of metallic struts, a uniform distribution was characterized. PCB demonstrated an equivalent biological effect in DES-ISR without significantly increasing inflammation. © 2015 Wiley Periodicals, Inc.

Oscope identifies oscillatory genes in unsynchronized single-cell RNA-seq experiments.

Oscillatory gene expression is fundamental to development, but technologies for monitoring expression oscillations are limited. We have developed a statistical approach called Oscope to identify and characterize the transcriptional dynamics of oscillating genes in single-cell RNA-seq data from an unsynchronized cell population. Applying Oscope to a number of data sets, we demonstrated its utility and also identified a potential artifact in the Fluidigm C1 platform.

Polybasic trafficking signal mediates golgi export, ER retention or ER export and retrieval based on membrane-proximity.

Trafficking of integral membrane proteins between the ER and Golgi complex, and protein sorting and trafficking between the TGN and endosomal/lysosomal compartments or plasma membranes, are dependent on cis-acting, linear amino acid sorting signals. Numerous sorting signals of this type have been identified in the cytoplasmic domains of membrane proteins, several of which rely on basic residues. A novel Golgi export signal that relies on a membrane-proximal polybasic motif (PBM) was recently identified in the reptilian reovirus p14 protein, a representative of an unusual group of bitopic fusion-associated small transmembrane (FAST) proteins encoded by fusogenic orthoreoviruses and responsible for cell-cell fusion and syncytium formation. Using immunofluorescence microscopy, cell surface immunofluorescence, and endoglycosidase H assays, we now show the p14 PBM can mediate several distinct trafficking functions depending on its proximity to the transmembrane domain (TMD). When present within 4-residues of the TMD it serves as a Golgi export signal, but when located at the C-terminus of the 68-residue p14 cytoplasmic endodomain it functions as an ER retention signal. The PBM has no effect on protein trafficking when located at an internal position in the cytoplasmic domain. When present in both membrane-proximal and -distal locations, the PBMs promote export to, and efficient retrieval from, the Golgi complex. Interestingly, the conflicting trafficking signals provided by two PBMs induces extensive ER tubulation and segregation of ER components. These studies highlight how a single trafficking signal in a simple transmembrane protein can have remarkably diverse, position-dependent effects on protein trafficking and ER morphogenesis.

Comparative RNA-seq analysis in the unsequenced axolotl: the oncogene burst highlights early gene expression in the blastema.

The salamander has the remarkable ability to regenerate its limb after amputation. Cells at the site of amputation form a blastema and then proliferate and differentiate to regrow the limb. To better understand this process, we performed deep RNA sequencing of the blastema over a time course in the axolotl, a species whose genome has not been sequenced. Using a novel comparative approach to analyzing RNA-seq data, we characterized the transcriptional dynamics of the regenerating axolotl limb with respect to the human gene set. This approach involved de novo assembly of axolotl transcripts, RNA-seq transcript quantification without a reference genome, and transformation of abundances from axolotl contigs to human genes. We found a prominent burst in oncogene expression during the first day and blastemal/limb bud genes peaking at 7 to 14 days. In addition, we found that limb patterning genes, SALL genes, and genes involved in angiogenesis, wound healing, defense/immunity, and bone development are enriched during blastema formation and development. Finally, we identified a category of genes with no prior literature support for limb regeneration that are candidates for further evaluation based on their expression pattern during the regenerative process.

Correlation of histologic and clinical images to determine the diagnostic value of fluorescein angiography for studying retinal capillary detail.

PURPOSE: To delineate morphometric and quantitative features of the capillary image derived from high-resolution fundus fluorescein angiography (FFA) and consequently determine the diagnostic value of FFA for studying the retinal capillary circulation. METHODS: Retinal capillary images obtained from healthy young subjects using high-resolution FFA were compared with confocal scanning laser microscopic capillary images derived from the retinas of age-matched human donors. Confocal microscopic images were acquired from retinal flatmount tissue after central retinal artery cannulation, perfusion fixation, and antibody labeling. Capillary images from equivalent retinal regions were morphologically and quantitatively analyzed in both groups. RESULTS: Ten human subjects (mean age, 27.4 years) were used for FFA studies, and five cadaveric eyes (mean donor age, 26.5 years) were used for histologic studies. In histologic specimens the density of the superficial capillary network was significantly greater than that of the deep capillary network. Despite use of a healthy young population, only 30% of high-resolution FFA studies provided clear capillary images. The configuration of the capillary network in FFA images was comparable to the superficial capillary network in confocal microscope images; however, the density of the capillary network in FFA images was consistently lower than that of histologic images. CONCLUSIONS: FFA provides incomplete morphologic information about the superficial capillary network and even less information about the deep capillary network. Caution should, therefore, be exercised when using FFA data to extrapolate information about microvascular histopathologic processes. The usefulness of newer technology for studying retinal capillary detail should be investigated.

British-English norms and naming times for a set of 539 pictures: the role of age of acquisition.

In the present study, we presented picture-naming latencies along with ratings for a set of important characteristics of pictures and picture names: age of acquisition, frequency, picture-name agreement, name agreement, visual complexity, familiarity, and word length. The validity of these data was established by calculating correlations with previous studies. Regression analyses show that our ratings account for a larger amount of variance in RTs than do previous data. RTs were predicted by all variables except complexity and length. A complete database presenting details about all of these variables is available in the supplemental materials, downloadable from http://brm.psychonomic-journals.org/content/supplemental.

Photodynamic Therapy with Verteporfin for Corneal Neovascularisation.

Corneal neovascularization can be a difficult problem to treat. The authors describe a patient with lipid keratopathy secondary to corneal neovascularization treated with photodynamic therapy. Six months following treatment the neovascularization has not returned and the lipid keratopathy has not increased in size. No significant side effects from the treatment occurred. Photodynamic therapy with Verteporfin was a useful treatment modality in this case of corneal neovascularization with associated lipid keratopathy.

Different activities of the reovirus FAST proteins and influenza hemagglutinin in cell-cell fusion assays and in response to membrane curvature agents.

The reovirus fusion-associated small transmembrane (FAST) proteins evolved to induce cell-cell, rather than virus-cell, membrane fusion. It is unclear whether the FAST protein fusion reaction proceeds in the same manner as the enveloped virus fusion proteins. We now show that fluorescence-based cell-cell and cell-RBC hemifusion assays are unsuited for detecting lipid mixing in the absence of content mixing during FAST protein-mediated membrane fusion. Furthermore, membrane curvature agents that inhibit hemifusion or promote pore formation mediated by influenza hemagglutinin had no effect on p14-induced cell-cell fusion, even under conditions of limiting p14 concentrations. Standard assays used to detect fusion intermediates induced by enveloped virus fusion proteins are therefore not applicable to the FAST proteins. These results suggest the possibility that the nature of the fusion intermediates or the mechanisms used to transit through the various stages of the fusion reaction may differ between these distinct classes of viral fusogens.

Intravitreal bevacizumab (Avastin) as a treatment of the neovascular complications of laser-induced chorioretinal anastomosis for nonischaemic central retinal vein occlusion.

PURPOSE: To describe the use of intravitreal bevacizumab followed by sectorial retinal photocoagulation to treat the neovascular complications of laser-induced chorioretinal anastomosis (L-CRA) for nonischaemic central retinal vein occlusion (CRVO). METHODS: Prospective interventional case series of three patients with nonischaemic CRVO who were treated with L-CRA. Patients were followed up every 2 weeks after the laser treatment. If neovascularization occurred at the site of the anastomosis, intravitreal bevacizumab (1.25 mg) was injected followed by laser photocoagulation to areas of retinal ischaemia and the area of retina anterior to the L-CRA 1 week later. Fluorescein angiography was performed to confirm the presence of neovascularization. Best-corrected visual acuity measurements were performed at every visit. RESULTS: Three patients (one woman, two men) with a mean age of 76.3 years developed neovascularization at the L-CRA site and underwent treatment as described with a mean follow-up time of 7 months. The neovascularization developed within 1 month after the laser anastomosis in all three cases. All patients only required one intravitreal bevacizumab injection to control the neovascularization. No complications of the intravitreal injections were noted. CONCLUSIONS: Intravitreal bevacizumab appears to be an effective tool in the immediate control of neovascularization following L-CRA for nonischaemic CRVO. This appears to cause immediate regression of the neovascular frond and allows time for the laser, which is applied subsequently to have its effect.

Enhanced fusion pore expansion mediated by the trans-acting Endodomain of the reovirus FAST proteins.

The reovirus fusion-associated small transmembrane (FAST) proteins are virus-encoded membrane fusion proteins that function as dedicated cell-cell fusogens. The topology of these small, single-pass membrane proteins orients the majority of the protein on the distal side of the membrane (i.e., inside the cell). We now show that ectopic expression of the endodomains of the p10, p14, and p15 FAST proteins enhances syncytiogenesis induced by the full-length FAST proteins, both homotypically and heterotypically. Results further indicate that the 68-residue cytoplasmic endodomain of the p14 FAST protein (1) is endogenously generated from full-length p14 protein expressed in virus-infected or transfected cells; (2) enhances syncytiogenesis subsequent to stable pore formation; (3) increases the syncytiogenic activity of heterologous fusion proteins, including the differentiation-dependent fusion of murine myoblasts; (4) exerts its enhancing activity from the cytosol, independent of direct interactions with either the fusogen or the membranes being fused; and (5) contains several regions with protein-protein interaction motifs that influence enhancing activity. We propose that the unique evolution of the FAST proteins as virus-encoded cellular fusogens has allowed them to generate a trans-acting, soluble endodomain peptide to harness a cellular pathway or process involved in the poorly understood process that facilitates the transition from microfusion pores to macrofusion and syncytiogenesis.

Aquareovirus effects syncytiogenesis by using a novel member of the FAST protein family translated from a noncanonical translation start site.

As nonenveloped viruses, the aquareoviruses and orthoreoviruses are unusual in their ability to induce cell-cell fusion and syncytium formation. While an extraordinary family of fusion-associated small transmembrane (FAST) proteins is responsible for orthoreovirus syncytiogenesis, the basis for aquareovirus-induced syncytiogenesis is unknown. We now report that the S7 genome segment of an Atlantic salmon reovirus is polycistronic and uses a noncanonical CUG translation start codon to produce a 22-kDa integral membrane protein responsible for syncytiogenesis. The aquareovirus p22 protein represents a fourth distinct member of the FAST family with a unique repertoire and arrangement of structural motifs.

Ophthalmic imaging today: an ophthalmic photographer's viewpoint - a review.

Ophthalmic imaging has changed dramatically since the 1960s with increasingly complex technologies now available. Arguably, the greatest changes have been the development of the digital camera and the speed, processing power and storage of electronic data. Already, ophthalmic practices in many major institutions overseas have paperless medium storage and electronically generated reporting from all equipment that use a computer interface. It is hard to remember the widespread use of photographic film with its attendant costs, or even to remember the days before optical coherence tomography (OCT). These latest technical improvements in ophthalmic imaging are now standard in large Australian institutions and becoming more widespread in smaller private practices. The technicians that operate and maintain this ever-increasing plethora of gadgetry have seen their work practices change from the darkroom to the complexities of data-based imaging and storage. It is a fitting time to examine the contemporary state of ophthalmic imaging and what lies on the horizon as we move towards 2020.

Sling distress: a subanalysis of the IVS tapes from the SUSPEND trial.

AIM: To study the incidence of erosions and tape infections following the use of intravaginal slingplasty (IVS) treatment for stress urinary incontinence after the SUSPEND trial period of 30 months. This subanalysis was carried out because of concerns regarding high percentage of delayed sling erosions and infections during follow up of the patients who participated in the trial. MATERIALS AND METHODS: The subanalysis patient group consisted of all IVS patients drawn from the SUSPEND randomised control trial that compared the safety and efficacy of three types of suburethral slings, TVT, SPARC and IVS, for the treatment of urodynamic stress incontinence. RESULTS: A total of 62 patients were reviewed during this study conducted from April 2002 to May 2003. Continence was achieved in 88% the patients. A total of eight (13%) sling erosions were found requiring sling removal. Forty-eight (77.4%) patients were followed up at 12 months with one case of erosion (1.7%). Twenty-nine (46.8%) of the 62 patients were followed up between 12 and 34 months, and seven cases of sling erosions were diagnosed. One patient had purulent suprapubic sinus, five patients had foul-smelling discharge, and one had recurrent urinary tract infection associated with pain and discharge. After the slings were removed the patients had no further symptoms. However, three of them had recurrent stress urinary incontinence. DISCUSSION/CONCLUSION: The delayed presentation of the sling erosion from this subanalysis is a concern, and pelvic reconstructive surgeons using IVS need to be aware of the delayed presentations we found in our cohort of patients.

Leaky scanning and scanning-independent ribosome migration on the tricistronic S1 mRNA of avian reovirus.

The S1 genome segments of avian and Nelson Bay reovirus encode tricistronic mRNAs containing three sequential partially overlapping open reading frames (ORFs). The translation start site of the 3'-proximal ORF encoding the sigmaC protein lies downstream of two ORFs encoding the unrelated p10 and p17 proteins and more than 600 nucleotides distal from the 5'-end of the mRNA. It is unclear how translation of this remarkable tricistronic mRNA is regulated. We now show that the p10 and p17 ORFs are coordinately expressed by leaky scanning. Translation initiation events at these 5'-proximal ORFs, however, have little to no effect on translation of the 3'-proximal sigmaC ORF. Northern blotting, insertion of upstream stop codons or optimized translation start sites, 5'-truncation analysis, and poliovirus 2A protease-mediated cleavage of eIF4G indicated sigmaC translation derives from a full-length tricistronic mRNA using a mechanism that is eIF4G-dependent but leaky scanning- and translation reinitiation-independent. Further analysis of artificial bicistronic mRNAs failed to provide any evidence that sigmaC translation derives from an internal ribosome entry site. Additional features of the S1 mRNA and the mechanism of sigmaC translation also differ from current models of ribosomal shunting. Translation of the tricistronic reovirus S1 mRNA, therefore, is dependent both on leaky scanning and on a novel scanning-independent mechanism that allows translation initiation complexes to efficiently bypass two functional upstream ORFs.

Comparison of the vascular responses to balloon-expandable stenting in the coronary and peripheral circulations: long-term results in an animal model using the TriMaxx stent.

OBJECTIVE: The clinical results after stenting in the coronary and peripheral circulations are vastly different. Possible explanations for this discrepancy include generally longer and more complex lesions in the periphery, variable vascular responses to injury according to anatomic location, disparate blood flow rates, and impedance in coronary vs skeletal smooth muscle beds, or phenotypic differences in neointimal hyperplasia and remodeling. This study examined the long-term results (6 months) after implantation of phosphorylcholine-coated balloon-expandable stents in a porcine model of experimental in-stent coronary and peripheral arterial restenosis. METHODS: Forty-eight stainless steel-tantalum-stainless steel composite balloon-expandable stents coated with phosphorylcholine (TriMaxx stent, Abbott Laboratories, Abbott Park, Ill) were implanted in the coronary (3.0 x 15 mm) or larger femoral arteries (4.0 x 38 mm) of Yorkshire crossbred swine to achieve a 1.1:1 stent-to-artery ratio. After 28, 90, or 180 days, the arteries were excised, perfusion-fixed at 100 mm Hg, sectioned, and stained with hematoxylin and eosin for morphometric evaluation. RESULTS: One animal did not survive to euthanasia; all arteries in surviving animals were patent. No significant differences were found in mean injury or inflammation scores among the groups or time points. The larger femoral arteries generated more neointimal area over time than the coronary arteries. The neointimal area in coronary arteries was 2.76 +/- 0.71, 1.75 +/- 0.42, and 1.83 +/- 0.19 mm(2) at 28, 90, and 180 days, respectively, and 5.20 +/- 0.97, 3.11 +/- 0.53, and 5.10 +/- 0.80 mm(2) in the femoral arteries (P < .05 coronary vs femoral at 180 days). This led to statistically significantly increased percent area stenosis at 180 days (coronary 27% +/- 4% vs femoral 45% +/- 5%; P < .05). CONCLUSIONS: The vascular response to balloon-expandable stenting in the coronary and peripheral circulations is different. After 6 months, neointimal hyperplasia and stent-induced stenosis were increased in peripheral porcine arteries compared with coronary arteries.