Clinician communication strategies associated with increased uptake of the human papillomavirus (HPV) vaccine: A systematic review.

Human papillomavirus (HPV) is currently linked to almost 35,000 new cases of cancer in women and men each year in the United States. Gardasil-9 (Merck & Company), the only HPV vaccine now available in the United States, is nearly 100% effective at preventing precancers caused by oncogenic HPV types. In the United States, however, only about one half of adolescents are up to date with HPV vaccination. It is well known that health care clinicians' recommendations play a significant role in parents' decisions regarding HPV vaccination. A growing body of literature examines specific communication strategies for promoting uptake of the HPV vaccine. A comprehensive review of the evidence for each of these strategies is needed. The authors searched the PubMed, EMBASE, Cochrane Central Register of Controlled Trials, PsycINFO, Cumulative Index to Nursing and Allied Health Literature, and Web of Science Complete databases for original articles with a defined clinician communication strategy and an outcome of HPV vaccine uptake or intention to vaccinate (PROSPERO registry no. CRD42020107602). In total, 46 studies were included. The authors identified two main strategies with strong evidence supporting their positive impact on vaccine uptake: strong recommendation and presumptive recommendation. Determinations about a causal relationship were limited by the small numbers of randomized controlled trials. There is also opportunity for more research to determine the effects of motivational interviewing and cancer-prevention messaging.

Are all domains created equal? An exploration of stakeholder views on the concept of physical literacy.

BACKGROUND: Developing physical literacy at population levels provides a transformative appeal for those working in sport, health, education, recreation and physical activity settings. Interdisciplinary approaches to development of policy in this area is recommended. The purpose of this study was to gather empirical data from key stakeholders working with young people in areas related to physical literacy across the Republic of Ireland and Northern Ireland, to capture their current understanding and awareness of the physical literacy to help inform the development of the first all-island consensus statement for physical literacy. METHODS: A total of 1,241 participants (52% male), from a range of stakeholder groups (health, physical activity, sport, recreation and education) completed a researcher developed physical literacy questionnaire. A one-way MANOVA was carried out to investigate differences across stakeholder grouping in terms of perceived importance of three domains of physical literacy. Overlap of independent confidence intervals was analysed to determine importance of the physical literacy domains within stakeholder grouping. RESULTS: A majority (63%) of respondents indicated they were aware of an existing definition of physical literacy, but this varied by stakeholder group (e.g. 86% for higher education, versus 47% of coaches). Participants working in higher education (69%), or working as physical education specialists (67%), were more likely to rate themselves as experts or near experts in physical literacy, while coaches, education generalists, and decision makers were more likely rate themselves as having no expertise (9%, 12% and 12% respectively). Non-specialist teachers and physical education teachers rated the importance of all domains of physical literacy significantly higher than decision makers, and significantly higher than coaches in the cognitive and affective domains. All stakeholders significantly rated the importance of the physical/psychomotor domain of physical literacy higher than the affective or cognitive domains of physical literacy. CONCLUSIONS: Differences observed across stakeholder groups underline the importance of developing a shared vision for physical literacy, and the need to clarify and gain consensus on a definition of the term and its domains. Engaging and understanding the voice of stakeholders is critical in ensuring the relevance, ownership of and commitment to physical literacy statement operationalisation.

Conscientious objections, the nature of medicine, and the need for reformability.

The debate over whether the medical profession should accommodate its members' conscientious objections (COs) has raged on in the bioethics literature and on legislative floors for decades. Unfortunately, participants on all sides of the debate fail to distinguish among different types of CO, a failure that obstructs the view of which cases warrant accommodation and why. In this paper, we identify one type of CO that warrants consideration for accommodation, called Nature of Medicine COs (NoMCOs). NoMCOs involve the refusal of physicians to perform actions they reasonably judge to be contrary to the nature of medicine and their professional obligations. We argue that accommodating NoMCOs can be justified based on the profession's need to preserve reformability. Importantly, this previously underdeveloped position evades some of the concerns commonly raised by opponents of CO accommodations.

Kinetic Analysis of Transient Intermediates in the Mechanism of Prenyl-Flavin-Dependent Ferulic Acid Decarboxylase.

Ferulic acid decarboxylase catalyzes the decarboxylation of various substituted phenylacrylic acids to their corresponding styrene derivatives and CO2 using the recently discovered cofactor prenylated FMN (prFMN). The mechanism involves an unusual 1,3-dipolar cycloaddition reaction between prFMN and the substrate to generate a cycloadduct capable of undergoing decarboxylation. Using native mass spectrometry, we show the enzyme forms a stable prFMN-styrene cycloadduct that accumulates on the enzyme during turnover. Pre-steady state kinetic analysis of the reaction using ultraviolet-visible stopped-flow spectroscopy reveals a complex pattern of kinetic behavior, best described by a half-of-sites model involving negative cooperativity between the two subunits of the dimeric enzyme. For the reactive site, the cycloadduct of prFMN with phenylacylic acid is formed with a kapp of 131 s-1. This intermediate converts to the prFMN-styrene cycloadduct with a kapp of 75 s-1. Cycloelimination of the prFMN-styrene cycloadduct to generate styrene and free enzyme appears to determine kcat for the overall reaction, which is 11.3 s-1.

Love thy neighbour? Allocating vaccines in a world of competing obligations.

Although a safe, effective, and licensed coronavirus vaccine does not yet exist, there is already controversy over how it ought to be allocated. Justice is clearly at stake, but it is unclear what justice requires in the international distribution of a scarce vaccine during a pandemic. Many are condemning 'vaccine nationalism' as an obstacle to equitable global distribution. We argue that limited national partiality in allocating vaccines will be a component of justice rather than an obstacle to it. For there are role-based and community-embedded responsibilities to take care of one's own, which constitute legitimate moral reasons for some identity-related prioritisation. Furthermore, a good form of vaccine nationalism prioritises one's own without denying or ignoring duties derived from a principle of equal worth, according to which all persons, regardless of citizenship or identity, equally deserve vaccine-induced protection from COVID-19. Rather than dismissing nationalism as a tragic obstacle, it is necessary to acknowledge that a limited form of it is valuable and expresses moral commitments. Only then can one understand our world of competing obligations, a world where cosmopolitan duties of benevolence sometimes conflict with special obligations of community membership. Once these competing obligations are recognised as such, we can begin the work of designing sound ethical frameworks for achieving justice in the global distribution of a coronavirus vaccine and developing practical strategies for avoiding, mitigating or resolving conflicts of duty.

Institutional Approaches to Research Integrity in Ghana.

Research misconduct (RM) remains an important problem in health research despite decades of local, national, regional, and international efforts to eliminate it. The ultimate goal of every health research project, irrespective of setting, is to produce trustworthy findings to address local as well as global health issues. To be able to lead or participate meaningfully in international research collaborations, individual and institutional capacities for research integrity (RI) are paramount. Accordingly, this paper concerns itself not only with individuals' research skills but also with institutional and national policies and governance. Such policies and governance provide an ethical scaffold for the production of knowledge and structure incentives. This paper's operational definition of research therefore draws from Institute of Medicine's articulation of health research as an inquiry that aims to produce knowledge about the structure, processes, or effects of personal health services; and from an existing health systems framework. The paper reviews the research regulatory environment and the ethics apparatus in Ghana, and describes a project jointly undertaken by Ghanaian researchers in collaboration with New York University to assess the perceived adequacy of current institutional practices, opportunities, and incentives for promoting RI.

Simultaneous Observation of the Orientation and Activity of Surface-Immobilized Enzymes.

Surface immobilized enzymes have been widely used in many applications such as biosensors, biochips, biofuel production, and biofuel cell construction. Many factors dictate how enzymes' structure, activity, and stability may change when immobilized, including surface functionalization, immobilization chemistry, nature of the solid support, and enzyme surface density. To better understand how immobilization affects enzyme structure and activity, we have developed a method to measure both surface-sensitive protein vibrational spectra and enzymatic activity simultaneously. To accomplish this, an optical/fluorescence microscope was incorporated into a sum frequency generation (SFG) spectrometer. Using ß-glucosidase (ß-Glu) as a model system, enzymes were covalently tethered to a self-assembled monolayer surface using cysteine-maleimide chemistry. Their orientations were determined by SFG spectroscopy, with a single native cysteine residue oriented toward the functionalized surface, and activity measured simultaneously using a fluorogenic substrate resorufin ß-d-glucopyranoside, with a loss of activity of 53% as compared to comparable solution measurements. Measuring ß-Glu activity and orientation simultaneously provides more accurate information for designing and further improving enzymatic activity of surface-bound enzymes.

Informing Efforts to Develop Nitroreductase for Amine Production.

Nitroreductases (NRs) hold promise for converting nitroaromatics to aromatic amines. Nitroaromatic reduction rate increases with Hammett substituent constant for NRs from two different subgroups, confirming substrate identity as a key determinant of reactivity. Amine yields were low, but compounds yielding amines tend to have a large π system and electron withdrawing substituents. Therefore, we also assessed the prospects of varying the enzyme. Several different subgroups of NRs include members able to produce aromatic amines. Comparison of four NR subgroups shows that they provide contrasting substrate binding cavities with distinct constraints on substrate position relative to the flavin. The unique architecture of the NR dimer produces an enormous contact area which we propose provides the stabilization needed to offset the costs of insertion of the active sites between the monomers. Thus, we propose that the functional diversity included in the NR superfamily stems from the chemical versatility of the flavin cofactor in conjunction with a structure that permits tremendous active site variability. These complementary properties make NRs exceptionally promising enzymes for development for biocatalysis in prodrug activation and conversion of nitroaromatics to valuable aromatic amines. We provide a framework for identifying NRs and substrates with the greatest potential to advance.

Evidence for a 1,3-Dipolar Cyclo-addition Mechanism in the Decarboxylation of Phenylacrylic Acids Catalyzed by Ferulic Acid Decarboxylase.

Ferulic acid decarboxylase catalyzes the decarboxylation of phenylacrylic acid using a newly identified cofactor, prenylated flavin mononucleotide (prFMN). The proposed mechanism involves the formation of a putative pentacyclic intermediate formed by a 1,3 dipolar cyclo-addition of prFMN with the α-ß double bond of the substrate, which serves to activate the substrate toward decarboxylation. However, enzyme-catalyzed 1,3 dipolar cyclo-additions are unprecedented and other mechanisms are plausible. Here we describe the use of a mechanism-based inhibitor, 2-fluoro-2-nitrovinylbenzene, to trap the putative cyclo-addition intermediate, thereby demonstrating that prFMN can function as a dipole in a 1,3 dipolar cyclo-addition reaction as the initial step in a novel type of enzymatic reaction.

Seasonal migration of marsupial megafauna in Pleistocene Sahul (Australia-New Guinea).

Seasonal two-way migration is an ecological phenomenon observed in a wide range of large-bodied placental mammals, but is conspicuously absent in all modern marsupials. Most extant marsupials are typically smaller in body size in comparison to their migratory placental cousins, possibly limiting their potential to undertake long-distance seasonal migrations. But what about earlier, now-extinct giant marsupial megafauna? Here we present new geochemical analyses which show that the largest of the extinct marsupial herbivores, the enormous wombat-like Diprotodon optatum, undertook seasonal, two-way latitudinal migration in eastern Sahul (Pleistocene Australia-New Guinea). Our data infer that this giant marsupial had the potential to perform round-trip journeys of as much as 200 km annually, which is reminiscent of modern East African mammal migrations. These findings provide, to our knowledge, the first evidence for repetitive seasonal migration in any metatherian (including marsupials), living or extinct, and point to an ecological phenomenon absent from the continent since the Late Pleistocene.

Mechanism of the Novel Prenylated Flavin-Containing Enzyme Ferulic Acid Decarboxylase Probed by Isotope Effects and Linear Free-Energy Relationships.

Ferulic acid decarboxylase from Saccharomyces cerevisiae catalyzes the decarboxylation of phenylacrylic acid to form styrene using a newly described prenylated flavin mononucleotide cofactor. A mechanism has been proposed, involving an unprecedented 1,3-dipolar cyclo-addition of the prenylated flavin with the αâ•ß bond of the substrate that serves to activate the substrate toward decarboxylation. We measured a combination of secondary deuterium kinetic isotope effects (KIEs) at the α- and ß-positions of phenylacrylic acid together with solvent deuterium KIEs. The solvent KIE is 3.3 on Vmax/KM but is close to unity on Vmax, indicating that proton transfer to the product occurs before the rate-determining step. The secondary KIEs are normal at both the α- and ß-positions but vary in magnitude depending on whether the reaction is performed in H2O or D2O. In D2O, the enzyme catalyzed the exchange of deuterium into styrene; this reaction was dependent on the presence of bicarbonate. This observation implies that CO2 release must occur after protonation of the product. Further information was obtained from a linear free-energy analysis of the reaction through the use of a range of para- and meta-substituted phenylacrylic acids. Log(kcat/KM) for the reaction correlated well with the Hammett σ(-) parameter with ρ = -0.39 ± 0.03; r(2) = 0.93. The negative ρ value and secondary isotope effects are consistent with the rate-determining step being the formation of styrene from the prenylated flavin-product adduct through a cyclo-elimination reaction.

TUMORS OF THE NONPIGMENTED EPITHELIUM OF THE CILIARY BODY: The Lorenz E. Zimmerman Tribute Lecture.

BACKGROUND: In 1970, Dr. Lorenz Zimmerman delivered the Norman McAlister Gregg Lecture entitled "The remarkable polymorphism of tumors of the ciliary epithelium." Therein, he proposed a classification of these tumors that included congenital lesions (mainly medulloepithelioma) and acquired lesions (mainly adenoma and adenocarcinoma). The classification was based on histopathologic observations without detailed clinical information. METHODS: Review of the published literature and personal experience with tumors of the nonpigmented ciliary body epithelium. RESULTS: Since 1970, further observations through clinical examination and advanced testing with ultrasound biomicroscopy, anterior segment optical coherence tomography, and magnetic resonance imaging have expanded our knowledge regarding tumors of the nonpigmented ciliary body epithelium. Regarding medulloepithelioma, we have learned of the common associated features of neovascular glaucoma, retrolenticular neoplastic or vascular cyclitic membrane, intralesional cysts, response to radiotherapy, and association with Dicer-1 mutation. Regarding adenoma/adenocarcinoma, improved management with surgical resection (sparing globe) can be achieved. Fuchs adenoma, also termed coronal adenoma, is commonly found histopathologically, despite its rare clinical visualization, and should be added to the Zimmerman classification. CONCLUSION: Since Zimmerman's report on histopathologic features of tumors of the nonpigmented ciliary body epithelium, there have been numerous publications and further observations on the clinical features and management of these intriguing neoplasms.

Choroidal melanoma: clinical features, classification, and top 10 pseudomelanomas.

PURPOSE OF REVIEW: To review the current features and classification of choroidal melanoma, and to identify the lesions that clinically simulate choroidal melanoma (pseudomelanoma). RECENT FINDINGS: Uveal melanoma is a serious life-threatening intraocular malignancy, most often found in Caucasians (98%) and primarily involving the choroid (90%), ciliary body (7%), or iris (2%). This review will concentrate on choroidal melanoma. At diagnosis, choroidal melanoma usually appears as a pigmented (85%) tumor underlying the retina with a median basal dimension of 11 mm and a mean thickness of 4.5 mm. The American Joint Committee on Cancer classification allows for categorization and staging of melanoma. Following ocular therapy, adjuvant systemic therapy is provided for patients with high-risk melanoma who demonstrate alterations in chromosomes 3, 6, and 8 or those with class 2 on gene-expression profiling, detected by needle biopsy or solid tumor biopsy. The prognosis of choroidal melanoma depends most importantly on the genetic alterations and tumor size. Every millimeter increase in thickness leads to a 5% increased risk for metastasis. The leading conditions that simulate choroidal melanoma include choroidal nevus, peripheral exudative hemorrhagic chorioretinopathy, congenital hypertrophy of the retinal pigment epithelium (RPE), hemorrhagic RPE detachment, choroidal hemangioma, age-related macular degeneration, RPE hyperplasia, and others. These pseudomelanomas can be differentiated from choroidal melanoma by their unique clinical features. SUMMARY: Choroidal melanoma is a serious malignancy with characteristic features. Early detection and therapy is important. Pseudomelanomas can lead to diagnostic confusion; however, clinical features aid in differentiation.

Ethical Challenges of Advances in Vaccine Delivery Technologies.

Strategies to address misinformation and hesitancy about vaccines, including the fear of needles, and to overcome obstacles to access, such as the refrigeration that some vaccines demand, strongly suggest the need to develop new vaccine delivery technologies. But, given widespread distrust surrounding vaccination, these new technologies must be introduced to the public with the utmost transparency, care, and community involvement. Two emerging technologies, one a skin-patch vaccine and the other a companion dye and detector, provide excellent examples of greatly improved delivery technologies for which such a careful approach should be developed in order to increase vaccine uptake. Defusing fears and conspiracy mongering must be a key part of their rollout.

Analysis and Potential Value of Compounds Extracted From Star Ruby, Rio Red, and Ruby Red Grapefruit, and Grapefruit Juice Processing Residues via Steam Explosion.

Culled whole grapefruit (WG) and grapefruit juice processing residues (GP) are currently incorporated into low-cost animal feed. If individual chemical components found within these side streams could be recovered as high-value coproducts, this would improve the overall value of the grapefruit crop. In this study, pectic hydrocolloids, sugars, volatiles, phenolics, and flavonoids were extracted from Star Ruby, Rio Red, and Ruby Red GP and WG using a continuous pilot scale steam explosion system. Up to 97% of grapefruit juice oils and peel oils could be volatilized and contained 87-94% d-limonene. The recovery of pectin, as determined by galacturonic acid content, was between 2.06 and 2.72 g 100 g-1. Of the phenolics and flavonoids analyzed in this study, narirutin and naringin were extracted in the amounts of up to 10,000 and 67,000 µg g-1, respectively.

Steam Explosion (STEX) of Citrus × Poncirus Hybrids with Exceptional Tolerance to Candidatus Liberibacter Asiaticus (CLas) as Useful Sources of Volatiles and Other Commercial Products.

Florida citrus production has declined 75% due to Huanglongbing (HLB), a disease caused by the pathogenic bacterium Candidatus Liberibacter asiaticus (CLas). Methods to combat CLas are costly and only partially effective. The cross-compatible species Poncirus trifoliata and some of its hybrids are known to be highly tolerant to CLas, and thus can potentially serve as an alternative feedstock for many citrus products. To further investigate the commercial potential of citrus hybrids, three citrus hybrids, US-802, US-897, and US-942, were studied for their potential as feedstocks for citrus co-products using steam explosion (STEX) followed by water extraction. Up to 93% of sugars were recovered. US-897 and US-942 have similar volatile profiles to that of the commercial citrus fruit types and as much as 85% of these volatiles could be recovered. Approximately 80% of the pectic hydrocolloids present in all three hybrids could be obtained in water washes of STEX material. Of the phenolics identified, the flavanone glycosides, i.e., naringin, neohesperidin, and poncirin were the most abundant quantitatively in these hybrids. The ability to extract a large percentage of these compounds, along with their inherent values, make US-802, US-897, and US-942 potentially viable feedstock sources for citrus co-products in the current HLB-blighted environment.