Exploring the future adult vaccine landscape-crowded schedules and new dynamics.

Amidst the backdrop of the COVID-19 pandemic, vaccine innovation has garnered significant attention, but this field was already on the cusp of a groundbreaking renaissance. Propelling these advancements are scientific and technological breakthroughs, alongside a growing understanding of the societal and economic boons vaccines offer, particularly for non-pediatric populations like adults and the immunocompromised. In a departure from previous decades where vaccine launches could be seamlessly integrated into existing processes, we anticipate potentially than 100 novel, risk-adjusted product launches over the next 10 years in the adult vaccine market, primarily addressing new indications. However, this segment is infamous for its challenges: low uptake, funding shortfalls, and operational hurdles linked to delivery and administration. To unlock the societal benefits of this burgeoning expansion, we need to adopt a fresh perspective to steer through the dynamics sparked by the rapid growth of the global adult vaccine market. This article aims to provide that fresh perspective, offering a detailed analysis of the anticipated number of adult vaccine approvals by category and exploring how our understanding of barriers to adult vaccine uptake might evolve. We incorporated pertinent insights from external stakeholder interviews, spotlighting shifting preferences, perceptions, priorities, and decision-making criteria. Consequently, this article aspires to serve as a pivotal starting point for industry participants, equipping them with the knowledge to skillfully navigate the anticipated surge in both volume and complexity.

Levels of complement factor H-related 4 protein do not influence susceptibility to age-related macular degeneration or its course of progression.

Dysregulation of the alternative pathway (AP) of the complement system is a significant contributor to age-related macular degeneration (AMD), a primary cause of irreversible vision loss worldwide. Here, we assess the contribution of the liver-produced complement factor H-related 4 protein (FHR-4) to AMD initiation and course of progression. We show that FHR-4 variation in plasma and at the primary location of AMD-associated pathology, the retinal pigment epithelium/Bruch's membrane/choroid interface, is entirely explained by three independent quantitative trait loci (QTL). Using two distinct cohorts composed of a combined 14,965 controls and 20,741 cases, we ascertain that independent QTLs for FHR-4 are distinct from variants causally associated with AMD, and that FHR-4 variation is not independently associated with disease. Additionally, FHR-4 does not appear to influence AMD progression course among patients with disease driven predominantly by AP dysregulation. Modulation of FHR-4 is therefore unlikely to be an effective therapeutic strategy for AMD.

Outlook of pandemic preparedness in a post-COVID-19 world.

The COVID-19 pandemic was met with rapid, unprecedented global collaboration and action. Even still, the public health, societal, and economic impact may be felt for years to come. The risk of another pandemic occurring in the next few decades is ever-present and potentially increasing due to trends such as urbanization and climate change. While it is difficult to predict the next pandemic pathogen threat, making reasonable assumptions today and evaluating prior efforts to plan for and respond to disease outbreaks and pandemics may enable a more proactive, effective response in the future. Lessons from the COVID-19 response and pandemic influenza preparedness underscore the importance of strengthening surveillance systems, investing in early-stage research on pandemic pathogens and development of platform technologies, and diversifying response plans across a range of tactics to enable earlier access to safe and effective interventions in the next pandemic. Further, sustaining the robust vaccine manufacturing capacity built because of COVID-19 will keep it ready for rapid response in the future. These actions will not be successful without improved global coordination and collaboration. Everyone, including the biopharmaceutical industry, has a role to play in pandemic preparedness, and working together will ensure that the most lives are saved in the next pandemic.

Longitudinal Aortic Root Dilatation in Collegiate American-Style Football Athletes.

Background Clinically relevant aortic dilatation (>40 mm) and increased cardiovascular risk are common among retired professional American-style football athletes. Among younger athletes, the effect of American-style football participation on aortic size is incompletely understood. We sought to determine changes in aortic root (AR) size and associated cardiovascular phenotypes across the collegiate career. Methods and Results This was a multicenter, longitudinal repeated-measures observational cohort study of athletes across 3 years of elite collegiate American-style football participation. A total of 247 athletes (119 [48%] Black, 126 [51%] White, 2 [1%] Latino; 91 [37%] linemen, 156 [63%] non-linemen) were enrolled as freshmen and studied at pre- and postseason year 1, postseason year 2 (N=140 athletes), and postseason year 3 (N=82 athletes). AR size was measured with transthoracic echocardiography. AR diameter increased over the study period from 31.7 (95% CI, 31.4-32.0) to 33.5 mm (95% CI, 33.1-33.8; P<0.001). No athlete developed an AR ≥40 mm. Athletes also demonstrated increased weight (cumulative mean Δ, 5.0 [95% CI, 4.1-6.0] kg, P<0.001), systolic blood pressure (cumulative mean Δ, 10.6 [95% CI, 8.0-13.2] mm Hg, P<0.001), pulse wave velocity (cumulative mean Δ, 0.43 [95% CI, 0.31-0.56] m/s, P<0.001), and left ventricular mass index (cumulative mean Δ, 21.2 [95% CI, 19.2-23.3] g/m2, P<0.001), and decreased E' velocity (cumulative mean Δ, -2.4 [95%CI, -2.9 to -1.9] cm/s, P<0.001). Adjusting for height, player position, systolic blood pressure, and diastolic blood pressure, higher weight (ß=0.030, P=0.003), pulse wave velocity (ß=0.215, P=0.02), and left ventricular mass index (ß=0.032, P<0.001) and lower E' (ß=-0.082, P=0.001) were associated with increased AR diameter. Conclusions Over the collegiate American-style football career, athletes demonstrate progressive AR dilatation associated with cardiac and vascular functional impairment. Future studies delineating aortic outcomes are necessary to determine whether AR dilation is indicative of maladaptive vascular remodeling in this population.

Experiences and Challenges of African American and Sub-Saharan African Immigrant Black Women in Completing Pap Screening: a Mixed Methods Study.

BACKGROUND: Understanding Black women's Papanicolaou (Pap) screening experiences can inform efforts to reduce cancer disparities. This study examined experiences among both US-born US Black women and Sub-Saharan African immigrant women. METHOD: Using a convergent parallel mixed methods design, Black women born in the USA and in Sub-Saharan Africa age 21-65 years were recruited to participate in focus groups and complete a 25-item survey about patient-centered communication and perceived racial discrimination. Qualitative and quantitative data were integrated to provide a fuller understanding of results. RESULTS: Of the 37 participants, 14 were US-born and 23 were Sub-Saharan African-born Black women. The mean age was 40.0 ± 11.0, and 83.8% had received at least one Pap test. Five themes regarding factors that impact screening uptake emerged from the focus groups: (1) positive and negative experiences with providers; (2) provider communication and interaction; (3) individual barriers to screening uptake, (4) implicit bias, discrimination, and stereotypical views among providers, and (5) language barrier. Survey and focus group findings diverged on several points. While focus group themes captured both positive and negative experiences with provider communication, survey results indicated that most of both US-born and Sub-Saharan African-born women experienced positive patient-centered communication with health care providers. Additionally, during focus group sessions many participants described experiences of discrimination in health care settings, but less than a third reported this in the survey. CONCLUSION: Black women's health care experiences affect Pap screening uptake. Poor communication and perceived discrimination during health care encounters highlight areas for needed service improvement to reduce cervical cancer disparities.

Improving antibiotic use in hospitals: development of a digital antibiotic review tracking toolkit (DARTT) using the behaviour change wheel.

OBJECTIVE: To develop a theory-informed behaviour change intervention to promote appropriate hospital antibiotic use, guided by the Medical Research Council's complex interventions framework. METHODS: A phased approach was used, including triangulation of data from meta-ethnography and two qualitative studies. Central to intervention design was the generation of a robust theoretical basis using the Behaviour Change Wheel to identify relevant determinants of behaviour change and intervention components. Intervention content was guided by APEASE (Acceptability, Practicability, Effectiveness, Affordability, Side-effects, and Equity) criteria and coded using a Behaviour Change Technique Taxonomy. Stakeholders were involved throughout. RESULTS: From numerous modifiable prescribing behaviours identified, active 'antibiotic time-out' was selected as the target behaviour to help clinicians safely initiate antibiotic reassessment. Prescribers' capability, opportunity, and motivation were potential drivers for changing this behaviour. The design process resulted in the selection of 25 behaviour change techniques subsequently translated into intervention content. Integral to this work was the development and refinement of a Digital Antibiotic Review Tracking Toolkit. CONCLUSION: This novel work demonstrates how the Behaviour Change Wheel can be used with the Medical Research Council framework to develop a theory-based behaviour change intervention targeting barriers to timely hospital antibiotic reassessment. Future research will evaluate the Antibiotic Toolkit's feasibility and effectiveness.

The Role of the NLRP3 Inflammasome in Mediating Glomerular and Tubular Injury in Diabetic Nephropathy.

The NOD-like receptor protein 3 (NLRP3) inflammasome is a multi-protein signalling complex integral to the chronic inflammatory response, activated in response to sterile and non-sterile cellular damage. The assembly and activation of the NLRP3 inflammasome comprise a two-step process involving nuclear factor kappa B (NFkB)-mediated priming, followed by canonical, non-canonical or alternative signalling pathways. These result in the maturation and release of inflammatory cytokines interleukin 1 beta (IL1ß) and interleukin-18 (IL18), which are associated with chronic inflammatory conditions including diabetic kidney disease. Diabetic nephropathy is a condition affecting ∼40% of people with diabetes, the key underlying pathology of which is tubulointerstitial inflammation and fibrosis. There is growing evidence to suggest the involvement of the NLRP3 inflammasome in this chronic inflammation. Early deterioration of kidney function begins in the glomerulus, with tubular inflammation dictating the progression of late-stage disease. Priming and activation of the NLRP3 inflammasome have been linked to several clinical markers of nephropathy including proteinuria and albuminuria, in addition to morphological changes including mesangial expansion. Treatment options for diabetic nephropathy are limited, and research that examines the impact of directly targeting the NLRP3 inflammasome, or associated downstream components are beginning to gain favour, with several agents currently in clinical trials. This review will explore a role for NLRP3 inflammasome activation and signalling in mediating inflammation in diabetic nephropathy, specifically in the glomerulus and proximal tubule, before briefly describing the current position of therapeutic research in this field.

Risky business in Georgia's wild birds: contact rates between wild birds and backyard chickens is influenced by supplemental feed.

Backyard chickens are increasingly popular, and their husbandry varies widely. How backyard chickens are housed may influence the accessibility of chicken feed and water to wild birds, and thus, the contact rates between both groups. Increased contacts have implications for pathogen transmission; for instance, Newcastle disease virus or avian influenza virus may be transmitted to and from backyard chickens from contaminated water or feed. Given this potentially increased pathogen risk to wild birds and backyard chickens, we examined which wild bird species are likely to encounter backyard chickens and their resources. We performed a supplemental feeding experiment followed by observations at three sites associated with backyard chickens in North Georgia, USA. At each site, we identified the species of wild birds that: (a) shared habitat with the chickens, (b) had a higher frequency of detection relative to other species and (c) encountered the coops. We identified 14 wild bird species that entered the coops to consume supplemental feed and were considered high-risk for pathogen transmission. Our results provide evidence that contact between wild birds and backyard chickens is frequent and more common than previously believed, which has crucial epidemiological implications for wildlife managers and backyard chicken owners.

Enhancing clinician participation in quality improvement training: implementation and impact of an evidence-based initiative to maximise antenatal clinician participation in training regarding women's alcohol consumption during pregnancy.

BACKGROUND: There are significant challenges in ensuring sufficient clinician participation in quality improvement training. Clinician capability has been identified as a barrier to the delivery of evidence-based care. Clinician training is an effective strategy to address this barrier, however, there are significant challenges in ensuring adequate clinician participation in training. This study aimed to assess the extent of participation by antenatal clinicians in evidence-based training to address alcohol consumption during pregnancy, and to assess differences in participation by profession. METHODS: A 7-month training initiative based on six evidence-based principles was implemented in a maternity service in New South Wales, Australia. Descriptive statistics described participation in training (% attending: any training; six evidence-based principles of training; all principles). Regression analyses examined differences by profession. RESULTS: Almost all antenatal clinicians participated in some training (182/186; 98%); 69% participated in ≥1 h of training (µ = 88.2mins, SD:56.56). The proportion of clinicians participating in training that satisfied each of the six principles ranged from 35% (training from peers and experts) to 82% (training was educational and instructional). Only 7% participated in training that satisfied all principles. A significantly higher proportion of midwifery compared to medical clinicians participated in training satisfying five of the six training principles. CONCLUSIONS: A training initiative based on evidence-based principles resulted in almost all clinicians receiving some training and 69% participating in at least 1 h of training. Variability between professions suggests training needs to be tailored to such groups. Further research is required to determine possible associations with care delivery outcomes. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry, No. ACTRN12617000882325 (date registered: 16/06/2017).

Hypertension and Ventricular-Arterial Uncoupling in Collegiate American Football Athletes.

Background Ventricular-arterial (VA) coupling is defined as the ratio between arterial elastance (EA) and left ventricular elastance (ELV). VA uncoupling, as occurs in hypertensive heart disease, is associated with adverse outcomes. This study sought to determine the relationship between American football (AF)-associated hypertension and VA uncoupling. Methods and Results This was a multicenter, longitudinal, and repeated measures observational study of collegiate AF athletes across 3 years of AF participation. Of 200 freshman athletes initially enrolled, 142 (67 Black [47%]/75 White [53%], 58 linemen [41%]/84 nonlinemen [59%]) were prospectively studied with echocardiography and applanation tonometry. Primary echocardiographic VA coupling outcome measures were EA/ELV and ΔEA/ELV, with increased EA/ELV indicating VA uncoupling. Adjusting for race and player position, AF athletes demonstrated increased EA/ELV (mean [95% CI]Δ, 0.10 [0.04-0.15]; P=0.001) and systolic blood pressure (SBP) (mean [95% CI]Δ, 11.4 [8.3-14.5] mm Hg, P<0.001) over their collegiate AF careers. In combination with longitudinal VA uncoupling, hypertension prevalence (including both stage 1 and 2) increased from 54% at baseline to 77% (44% stage 2) at the end of the study period (P<0.001). In multivariable mixed-effects linear regression analysis, higher SBP (ß=0.021, P=0.02), lower E' (ß=-0.010, P=0.03), and worse global longitudinal strain (ß=0.036, P<0.001) were associated with higher EA/ELV. Increased SBP (ΔSBP, ß=0.029, P=0.02) and worsened global longitudinal strain (Δglobal longitudinal strain, ß=0.045, P<0.001) also predicted increased ΔEA/ELV. Conclusions VA uncoupling is associated with pathologically increased SBP and subclinical impairments in left ventricular systolic function in collegiate AF athletes, indicating a key mechanism underlying maladaptive cardiovascular phenotypes observed in this population. Future studies analyzing whether targeted clinical interventions improve VA coupling and health outcomes are warranted.

Association between genetic and socioenvironmental risk for schizophrenia during upbringing in a UK longitudinal cohort.

BACKGROUND: Associations of socioenvironmental features like urbanicity and neighborhood deprivation with psychosis are well-established. An enduring question, however, is whether these associations are causal. Genetic confounding could occur due to downward mobility of individuals at high genetic risk for psychiatric problems into disadvantaged environments. METHODS: We examined correlations of five indices of genetic risk [polygenic risk scores (PRS) for schizophrenia and depression, maternal psychotic symptoms, family psychiatric history, and zygosity-based latent genetic risk] with multiple area-, neighborhood-, and family-level risks during upbringing. Data were from the Environmental Risk (E-Risk) Longitudinal Twin Study, a nationally-representative cohort of 2232 British twins born in 1994-1995 and followed to age 18 (93% retention). Socioenvironmental risks included urbanicity, air pollution, neighborhood deprivation, neighborhood crime, neighborhood disorder, social cohesion, residential mobility, family poverty, and a cumulative environmental risk scale. At age 18, participants were privately interviewed about psychotic experiences. RESULTS: Higher genetic risk on all indices was associated with riskier environments during upbringing. For example, participants with higher schizophrenia PRS (OR = 1.19, 95% CI = 1.06-1.33), depression PRS (OR = 1.20, 95% CI = 1.08-1.34), family history (OR = 1.25, 95% CI = 1.11-1.40), and latent genetic risk (OR = 1.21, 95% CI = 1.07-1.38) had accumulated more socioenvironmental risks for schizophrenia by age 18. However, associations between socioenvironmental risks and psychotic experiences mostly remained significant after covariate adjustment for genetic risk. CONCLUSION: Genetic risk is correlated with socioenvironmental risk for schizophrenia during upbringing, but the associations between socioenvironmental risk and adolescent psychotic experiences appear, at present, to exist above and beyond this gene-environment correlation.

Inactivation of MS2 bacteriophage on copper film deployed in high touch areas of a public transport system.

Although SARS-CoV-2 is primarily an airborne risk, the COVID-19 pandemic also highlighted the need for self-disinfection surfaces that could withstand the demand of high occupant densities characteristic of public transportation systems. The aim of this study was to evaluate the durability and antiviral activity of a copper film deployed for 90 days in two high touch locations within an active metropolitan bus and railcar. The antiviral efficacy of this copper film after being deployed in transit vehicles for 90 days (deployed copper film) was then compared to new (unused) copper film to determine if frequent touches and cleaning protocols could decrease the efficacy of the copper films. Deployed copper film, new copper film, and aluminium foil (positive control) coupons were inoculated with ~1 × 106 MS2 virus particles, allowed a contact time of either 5- or 10-min, and analysed for residual viral infectiousness. On both new and deployed copper films, MS2 was completely inactivated (≥5 log reduction) at both time points. These results suggest that the copper film may provide the durability demanded by high touch public spaces while maintaining the antiviral activity necessary to reduce exposure risk and viral transmission via surfaces in public transportation settings.

Women's Knowledge of Bladder Health: What We Have Learned in the Prevention of Lower Urinary Tract Symptoms (PLUS) Research Consortium.

Purpose of Review: The goal of this manuscript is to review the current literature on bladder health education, summarize Prevention of Lower Urinary Tract Symptoms (PLUS) [50] findings on environmental factors that influence knowledge and beliefs about toileting and bladder function, and describe how PLUS work will contribute to improved understanding of women's bladder-related knowledge and inform prevention intervention strategies. Recent Findings: Analysis of focus group transcripts revealed the various ways women view, experience, and describe bladder function. In the absence of formal bladder health educational platforms, women appear to develop knowledge of normal and abnormal bladder function from a variety of social processes including environmental cues and interpersonal sources. Importantly, focus group participants expressed frustration with the absence of structured bladder education to inform knowledge and practices. Summary: There is a lack of bladder health educational programming in the USA, and it is unknown to what degree women's knowledge, attitudes, and beliefs influence their risk of developing lower urinary tract symptoms (LUTS). The PLUS Consortium RISE FOR HEALTH study will estimate the prevalence of bladder health in adult women and assess risk and protective factors. A Knowledge, Attitudes, and Beliefs (KAB) questionnaire will be administered to determine KAB around bladder function, toileting, and bladder-related behaviors, and examine the relationship of KAB to bladder health and LUTS. The data generated from PLUS studies will identify opportunities for educational strategies to improve bladder health promotion and well-being across the life course.

Clinical and Genetic Characteristics in Young, Glucocorticoid-Naive Boys With Duchenne Muscular Dystrophy.

BACKGROUND AND OBJECTIVES: Duchenne muscular dystrophy (DMD) is a paediatric neuromuscular disorder caused by mutations in the dystrophin gene. Geneotype-phenotype associations have been examined in glucocorticoid treated boys, but there are few data on the young glucocorticoid-naïve DMD population. A sample of young glucocorticoid-naïve DMD boys is described and genotype-phenotype associations are investigated. METHODS: Screening and baseline data were collected for all the participants in the Finding the Optimum Corticosteroid Regime for Duchenne Muscular Dystrophy (FOR-DMD)study, an international, multi-centre, randomized, double-blind, clinical trial comparing three glucocorticoid regimens in glucocorticoid-naïve, genetically confirmed boys with DMD between 4 and <8 years of age. RESULTS: One hundred and ninety-six boys were recruited. The meanage at randomization (+ standard deviation) was 5.8+ 1.0 years. The predominant mutation type was out of frame deletions 67.4%, (130/193) of which 68.5% (89/130) were amenable to exon skipping. The most frequent mutations were deletions amenable to exon 51 skipping 13.0% (25/193). Stop codon mutations accounted for 10.4% (20/193).The mean age at first parental concerns was 29.8 + 18.7 months, the mean age at genetic diagnosis was 53.9 + 21.9 months and the mean diagnostic delay was 25.9 + 18.2 months. The mean diagnostic delay for boys diagnosed following an incidental finding of isolated hyperCKemia (n=19) was 6.4 + 7.4 months. The mean ages at independent walking and talking in sentences were 17.1 + 4.2 and 29.0 + 10.7 months, respectively. Median height percentiles were below the 25th percentile regardless of age group. No genotype-phenotype associations were identified expect for boys with an exon 8 skippable deletions who had better performance on time to walk/run 10 meters (p=0.02)compared to boys with deletions not amenable to skipping. DISCUSSION: This study describes clinical and genetic characteristics of a sample of young glucocorticoid-naïve boys with DMD. A low threshold for CK testing can lead to an earlier diagnosis. Motor and speech delay were common presenting symptoms.The effects of low, pre-treatment height on growth and adults height requires further study. These findings may promote earlier recognition of DMD and inform study design for future clinical trials.

Specimen oriented intraoperative margin assessment in oral cavity and oropharyngeal squamous cell carcinoma.

OBJECTIVE: Evaluate the oncologic outcomes and cost analysis of transitioning to a specimen oriented intraoperative margin assessment protocol from a tumour bed sampling protocol in oral cavity (OCSCC) and oropharyngeal squamous cell carcinoma (OPSCC). STUDY DESIGN: Retrospective case series and subsequent prospective cohort study SETTING: Tertiary care academic teaching hospital SUBJECTS AND METHODS: Retrospective case series of all institutional T1-T2 OCSCC or OPSCC treated with primary surgery between January 1st 2009 - December 31st 2014. Kaplan-Meier survival estimates with log rank tests were used to compare patients based on final margin status. Cost analysis was performed for escalation of therapy due to positive final margins. Following introduction of a specimen derived margin protocol, successive prospective cohort study of T1-T4 OCSCC or OPSCC treated with primary surgery from January 1st 2017 - December 31st 2018. Analysis and comparison of both protocols included review of intraoperative margins, final pathology and treatment cost. RESULTS: Analysis of our intra-operative tumour bed frozen section protocol revealed 15 of 116 (12.9%) patients had positive final pathology margins, resulting in post-operative escalation of therapy for 14/15 patients in the form of re-resection (7/14), radiation therapy (6/14) and chemoradiotherapy (1/14). One other patient with positive final margins received escalated therapy for additional negative prognostic factors. Recurrence free survival at 3 years was 88.4 and 50.7% for negative and positive final margins respectively (p = 0.048). Implementation of a specimen oriented frozen section protocol resulted in 1 of 111 patients (0.9%) having positive final pathology margins, a statistically significant decrease (p < 0.001). Utilizing our specimen oriented protocol, there was an absolute risk reduction for having a final positive margin of 12.0% and relative risk reduction of 93.0%. Estimated cost avoidance applying the specimen oriented protocol to our previous cohort was $412,052.812017 CAD. CONCLUSION: Implementation of a specimen oriented intraoperative margin protocol provides a statistically significant decrease in final positive margins. This change in protocol leads to decreased patient morbidity by avoiding therapy escalation attributable only to positive margins, and avoids the economic costs of these treatments.