Heterogeneous Longitudinal Antibody Responses to Covid-19 mRNA Vaccination.

BACKGROUND: Public health measures to stem the coronavirus disease 2019 (COVID-19) pandemic are challenged by social, economic, health status, and cultural disparities that facilitate disease transmission and amplify its severity. Prior pre-clinical biomedical technologic advances in nucleic acid-based vaccination enabled unprecedented speed of conceptualization, development, production, and widespread distribution of mRNA vaccines that target SARS-CoV-2's Spike (S) protein. DESIGN: Twenty-five female and male volunteer fulltime employees at the Providence VA Medical Center participated in this study to examine longitudinal antibody responses to the Moderna mRNA-1273 vaccine. IgM-S and IgG-S were measured in serum using the Abbott IgM-S-Qualitative and IgG2-S-Quantitative chemiluminescent assays. RESULTS: Peak IgM responses after Vaccine Dose #1 were delayed in 6 (24%) and absent in 7 (28%) participants. IgG2-S peak responses primarily occurred 40 to 44 days after Vaccine Dose #1, which was also 11 to 14 days after Vaccine Dose #2. However, subgroups exhibited Strong (n = 6; 24%), Normal (n = 13; 52%), or Weak (n = 6; 24%) peak level responses that differed significantly from each other (P < .005 or better). The post-peak IgG2-S levels declined progressively, and within 6 months reached the mean level measured 1 month after Vaccine Dose #1. Weak responders exhibited persistently low levels of IgG2-S. Variability in vaccine responsiveness was unrelated to age or gender. CONCLUSION: Host responses to SARS-CoV-2-Spike mRNA vaccines vary in magnitude, duration and occurrence. This study raises concern about the lack of vaccine protection in as many as 8% of otherwise normal people, and the need for open dialog about future re-boosting requirements to ensure long-lasting immunity via mRNA vaccination versus natural infection.

C4 anatomy can evolve via a single developmental change.

C4 photosynthesis is a complex trait that boosts productivity in warm environments. Paradoxically, it evolved independently in numerous plant lineages, despite requiring specialised leaf anatomy. The anatomical modifications underlying C4 evolution have previously been evaluated through interspecific comparisons, which capture numerous changes besides those needed for C4 functionality. Here, we quantify the anatomical changes accompanying the transition between non-C4 and C4 phenotypes by sampling widely across the continuum of leaf anatomical traits in the grass Alloteropsis semialata. Within this species, the only trait that is shared among and specific to C4 individuals is an increase in vein density, driven specifically by minor vein development that yields multiple secondary effects facilitating C4 function. For species with the necessary anatomical preconditions, developmental proliferation of veins can therefore be sufficient to produce a functional C4 leaf anatomy, creating an evolutionary entry point to complex C4 syndromes that can become more specialised.

Evolutionary implications of C3 -C4 intermediates in the grass Alloteropsis semialata.

C4 photosynthesis is a complex trait resulting from a series of anatomical and biochemical modifications to the ancestral C3 pathway. It is thought to evolve in a stepwise manner, creating intermediates with different combinations of C4 -like components. Determining the adaptive value of these components is key to understanding how C4 photosynthesis can gradually assemble through natural selection. Here, we decompose the photosynthetic phenotypes of numerous individuals of the grass Alloteropsis semialata, the only species known to include both C3 and C4 genotypes. Analyses of δ(13) C, physiology and leaf anatomy demonstrate for the first time the existence of physiological C3 -C4 intermediate individuals in the species. Based on previous phylogenetic analyses, the C3 -C4 individuals are not hybrids between the C3 and C4 genotypes analysed, but instead belong to a distinct genetic lineage, and might have given rise to C4 descendants. C3 A. semialata, present in colder climates, likely represents a reversal from a C3 -C4 intermediate state, indicating that, unlike C4 photosynthesis, evolution of the C3 -C4 phenotype is not irreversible.

Cost effectiveness analysis of Year 2 of an elementary school-located influenza vaccination program-Results from a randomized controlled trial.

BACKGROUND: School-located vaccination against influenza (SLV-I) has the potential to improve current suboptimal influenza immunization coverage for U.S. school-aged children. However, little is known about SLV-I's cost-effectiveness. The objective of this study is to establish the cost-effectiveness of SLV-I based on a two-year community-based randomized controlled trial (Year 1: 2009-2010 vaccination season, an unusual H1N1 pandemic influenza season, and Year 2: 2010-2011, a more typical influenza season). METHODS: We performed a cost-effectiveness analysis on a two-year randomized controlled trial of a Western New York SLV-I program. SLV-I clinics were offered in 21 intervention elementary schools (Year 1 n = 9,027; Year 2 n = 9,145 children) with standard-of-care (no SLV-I) in control schools (Year 1 n = 4,534 (10 schools); Year 2 n = 4,796 children (11 schools)). We estimated the cost-per-vaccinated child, by dividing the incremental cost of the intervention by the incremental effectiveness (i.e., the number of additionally vaccinated students in intervention schools compared to control schools). RESULTS: In Years 1 and 2, respectively, the effectiveness measure (proportion of children vaccinated) was 11.2 and 12.0 percentage points higher in intervention (40.7 % and 40.4 %) than control schools. In year 2, the cost-per-vaccinated child excluding vaccine purchase ($59.88 in 2010 US $) consisted of three component costs: (A) the school costs ($8.25); (B) the project coordination costs ($32.33); and (C) the vendor costs excluding vaccine purchase ($16.68), summed through Monte Carlo simulation. Compared to Year 1, the two component costs (A) and (C) decreased, while the component cost (B) increased in Year 2. The cost-per-vaccinated child, excluding vaccine purchase, was $59.73 (Year 1) and $59.88 (Year 2, statistically indistinguishable from Year 1), higher than the published cost of providing influenza vaccination in medical practices ($39.54). However, taking indirect costs (e.g., averted parental costs to visit medical practices) into account, vaccination was less costly in SLV-I ($23.96 in Year 1, $24.07 in Year 2) than in medical practices. CONCLUSIONS: Our two-year trial's findings reinforced the evidence to support SLV-I as a potentially favorable system to increase childhood influenza vaccination rates in a cost-efficient way. Increased efficiencies in SLV-I are needed for a sustainable and scalable SLV-I program.

Risk factors associated with sacral stress fractures: a systematic review.

OBJECTIVES: The objective of this study was to examine and identify risk factors associated with the development of sacral stress fractures in order to improve diagnosis in clinical practice. METHODS: Electronic search strategies in PubMed, CINAHL, Scopus, and SPORTDiscus were combined with a hand search to identify articles for inclusion. Studies were considered if they described patient cases in which imaging confirmed diagnosis of a sacral stress fracture, and the diagnosis included whether the fracture was a sacral insufficiency or sacral fatigue stress fracture. RESULTS: In those that developed sacral insufficiency fractures, the risk factors that were most prevalent included osteoporosis, pelvic radiation therapy, rheumatoid arthritis, long-term corticosteroid therapy, and postmenopausal, each with a prevalence of 100%. Risk factors with 100% prevalence in those diagnosed with sacral fatigue fractures included recent increase in training intensity and deficient diet. DISCUSSION: A pattern of signs and symptoms are consistent among subjects with sacral stress fractures. Patients being unsuccessfully treated for low-back and buttock pain who fit the risk factor profiles for sacral stress fractures should be referred to a physician for further diagnostic workup.

Seasonal influenza vaccination at school: a randomized controlled trial.

BACKGROUND: Influenza vaccination coverage for U.S. school-aged children is below the 80% national goal. Primary care practices may not have the capacity to vaccinate all children during influenza vaccination season. No real-world models of school-located seasonal influenza (SLV-I) programs have been tested. PURPOSE: Determine the feasibility, sustainability, and impact of an SLV-I program providing influenza vaccination to elementary school children during the school day. DESIGN: In this pragmatic randomized controlled trial of SLV-I during two vaccination seasons, schools were randomly assigned to SLV-I versus standard of care. Seasonal influenza vaccine receipt, as recorded in the state immunization information system (IIS), was measured. SETTING/PARTICIPANTS: Intervention and control schools were located in a single western New York county. Participation (intervention or control) included the sole urban school district and suburban districts (five in Year 1, four in Year 2). INTERVENTION: After gathering parental consent and insurance information, live attenuated and inactivated seasonal influenza vaccines were offered in elementary schools during the school day. MAIN OUTCOME MEASURES: Data on receipt of ≥1 seasonal influenza vaccination in Year 1 (2009-2010) and Year 2 (2010-2011) were collected on all student grades K through 5 at intervention and control schools from the IIS in the Spring of 2010 and 2011, respectively. Additionally, coverage achieved through SLV-I was compared to coverage of children vaccinated elsewhere. Preliminary data analysis for Year 1 occurred in Spring 2010; final quantitative analysis for both years was completed in late Fall 2012. RESULTS: Results are shown for 2009-2010 and 2010-2011, respectively: Children enrolled in suburban SLV-I versus control schools had vaccination coverage of 47% vs 36%, and 52% vs 36% (p<0.0001 both years). In urban areas, coverage was 36% vs 26%, and 31% vs 25% (p<0.001 both years). On multilevel logistic analysis with three nested levels (student, school, school district) during both vaccination seasons, children were more likely to be vaccinated in SLV-I versus control schools; ORs were 1.6 (95% CI=1.4, 1.9; p<0.001) and 1.5 (95% CI=1.3, 1.8; p<0.001). CONCLUSIONS: Delivering influenza vaccine during school is a promising approach to improving pediatric influenza vaccination coverage. TRIAL REGISTRY: ClinicalTrials.govNCT01224301.

Cost effectiveness analysis of elementary school-located vaccination against influenza--results from a randomized controlled trial.

School-located vaccination against influenza (SLV-I) has been suggested to help meet the need for annual vaccination of large numbers of school-aged children with seasonal influenza vaccine. However, little is known about the cost and cost-effectiveness of SLV-I. We conducted a cost-analysis and a cost-effectiveness analysis based on a randomized controlled trial (RCT) of an SLV-I program implemented in Monroe County, New York during the 2009-2010 vaccination season. We hypothesized that SLV-I is more cost effective, or less-costly, compared to a conventional, office-located influenza vaccination delivery. First and second SLV-I clinics were offered in 21 intervention elementary schools (n=9027 children) with standard of care (no SLV-I) in 11 control schools (n=4534 children). The direct costs, to purchase and administer vaccines, were estimated from our RCT. The effectiveness measure, receipt of ≥1 dose of influenza vaccine, was 13.2 percentage points higher in SLV-I schools than control schools. The school costs ($9.16/dose in 2009 dollars) plus project costs ($23.00/dose) plus vendor costs excluding vaccine purchase ($19.89/dose) was higher in direct costs ($52.05/dose) than the previously reported mean/median cost [$38.23/$21.44 per dose] for providing influenza vaccination in pediatric practices. However SLV-I averted parent costs to visit medical practices ($35.08 per vaccine). Combining direct and averted costs through Monte Carlo Simulation, SLV-I costs were $19.26/dose in net costs, which is below practice-based influenza vaccination costs. The incremental cost-effectiveness ratio (ICER) was estimated to be $92.50 or $38.59 (also including averted parent costs). When additionally accounting for the costs averted by disease prevention (i.e., both reduced disease transmission to household members and reduced loss of productivity from caring for a sick child), the SLV-I model appears to be cost-saving to society, compared to "no vaccination". Our findings support the expanded implementation of SLV-I, but also the need to focus on efficient delivery to reduce direct costs.

Assessing the acceptability and feasibility of a school-located influenza vaccination program with third-party billing in elementary schools.

This study qualitatively assesses the acceptability and feasibility of a school-located vaccination for influenza (SLIV) project that was conducted in New York State in 2009-2011, from the perspectives of project participants with different roles. Fourteen in-depth semistructured interviews with participating schools' personnel and the mass vaccinator were tape-recorded and transcribed. Interviewees were randomly selected from stratified lists and included five principals, five school nurses, two school administrators, and two lead personnel from the mass vaccinator. A content analysis of transcripts from the interviews was completed and several themes emerged. All participants generally found the SLIV project acceptable. School personnel and the vaccinator viewed the SLIV project process as feasible and beneficial. However, the vaccinator identified difficulties with third-party billing as a potential threat to sustainability.

Increasing inner-city adult influenza vaccination rates: a randomized controlled trial.

OBJECTIVES: In a population of seniors served by urban primary care centers, we evaluated the effect of the practice-based intervention on influenza immunization rates and disparities in vaccination rates by race/ethnicity and insurance status. METHODS: A randomized controlled trial during 2003-2004 tested patient tracking/recall/outreach and provider prompts on improving influenza immunization rates. Patients aged > or = 65 years in six large inner-city primary care practices were randomly allocated to study or control group. Influenza immunization coverage was measured prior to enrollment and on the end date. RESULTS: At study end, immunization rates were greater for the intervention group than for the control group (64% vs. 22%, p < 0.0001). When controlling for other factors, the intervention group was more than six times as likely to receive influenza vaccine. The intervention was effective across gender, race/ ethnicity, age, and insurance subgroups. Among the intervention group, 3.5% of African Americans and 3.2% of white people refused influenza immunization. CONCLUSIONS: Patient tracking/recall/outreach and provider prompts were intensive but successful approaches to increasing seasonal influenza immunization rates among this group of inner-city seniors.

Influenza testing and antiviral prescribing practices among emergency department clinicians in 9 states during the 2006 to 2007 influenza season.

STUDY OBJECTIVE: Influenza causes significant widespread illness each year. Emergency department (ED) clinicians are often first-line providers to evaluate and make treatment decisions for patients presenting with influenza. We sought to better understand ED clinician testing and treatment practices in the Emerging Infections Program Network, a federal, state, and academic collaboration that conducts active surveillance for influenza-associated hospitalizations. METHODS: During 2007, a survey was administered to ED clinicians who worked in Emerging Infections Program catchment area hospitals' EDs. The survey encompassed the role of the clinician, years since completing clinical training, hospital type, influenza testing practices, and use of antiviral medications during the 2006 to 2007 influenza season. We examined factors associated with influenza testing and antiviral use. RESULTS: A total of 1,055 ED clinicians from 123 hospitals responded to the survey. A majority of respondents (85.3%; n=887) reported they had tested their patients for influenza during the 2006 to 2007 influenza season (Emerging Infections Program site range: 59.3 to 100%; P<.0001). When asked about antiviral medications, 55.7% (n=576) of respondents stated they had prescribed antiviral medications to some of their patients in 2006 to 2007 (Emerging Infections Program site range 32.9% to 80.3%; P<.0001). A positive association between influenza testing and prescribing antiviral medications was observed. Additionally, the type of hospital, location in which an ED clinician worked, and the number of years since medical training were associated with prescribing antiviral influenza medications. CONCLUSION: There is much heterogeneity in clinician-initiated influenza testing and treatment practices. Additional exploration of the role of hospital testing and treatment policies, clinicians' perception of influenza disease, and methods for educating clinicians about new recommendations is needed to better understand ED clinician testing and treatment decisions, especially in an environment of rapidly changing influenza clinical guidelines. Until influenza testing and treatment guidelines are better promulgated, clinicians may continue to test and treat influenza with inconsistency.

Preventability of invasive pneumococcal disease and assessment of current polysaccharide vaccine recommendations for adults: United States, 2001-2003.

UNLABELLED: BACKGROUND. To prevent Streptococcus pneumoniae infection among persons at highest risk for invasive pneumococcal disease (IPD), the pneumococcal polysaccharide vaccine (PPV) is currently recommended for persons >or=65 years old and persons 2-64 years old with certain underlying conditions. Policymakers have considered expanding recommendations for PPV to include persons who are 50-64 years old and additional populations at risk for IPD. Our objectives were to determine the proportion of IPD cases that might have been prevented if all persons with vaccine indications had been vaccinated and to evaluate new indications. METHODS: From 2001 to 2003, we performed a case series study of IPD in adults at 6 sites of the Active Bacterial Core surveillance-Emerging Infections Program Network. A case of IPD was defined as isolation of pneumococcus from a normally sterile site from a resident of 1 of the surveillance areas. RESULTS: Among 1878 case patients, 1558 (83%) had at least 1 current vaccine indication; of these, 968 case patients (62%) were unvaccinated. Adherence to existing vaccine recommendations would have prevented 21% of all cases. The proportions of all cases potentially prevented by each new indication were as follows: lowering the universal age of recommended vaccination to 50 years, 5.0%-7.0%; adding new risk-based indications to include current smoking, 1.5%-2.5%; former smoking, 0.4%-0.7%; black race, 1.0%-1.4%; and asthma, 0.3%-0.4%. CONCLUSIONS: Increasing vaccine coverage rates among persons with a current indication may prevent more cases than expanding existing indications. Of the potential new indications studied, the strategy that may prevent most cases is lowering the recommended age for universal vaccination to 50 years.

Why do not patients receive influenza vaccine in December and January?

BACKGROUND: Influenza vaccination levels in older patients have changed little since the mid-1990s. Despite frequent health care visits by a majority of older persons, many missed opportunities continue to occur. METHODS: Patients were eligible for the study if they were age 50 and older, had not received influenza vaccine during the current season and were making a scheduled visit to one of the 13 study sites in California, New York, or New Mexico for purposes other than vaccination. Through direct observation, we determined if office staff inquired about vaccination status, discussed vaccination, or both. We defined missed opportunities as failure to administer influenza vaccine to patients for whom it was indicated. RESULTS: Missed opportunities increased steadily from October to January (P < 0.0001), and were more common when there was no inquiry or discussion (P < 0.00001), among patients aged 50-64 (P < 0.0001) and in California and New Mexico (P = 0.001). A classification tree analysis revealed that lack of inquiry and week of visit contributed most to missed opportunities. DISCUSSION: Early in the vaccination season, missed opportunities were uncommon and specific inquiries into or discussion of vaccination did not appear necessary. In December and January, patients tended to be vaccinated only when vaccination was addressed during the visit. Efforts to remind patients about vaccination later in the vaccination season may be essential to achieving higher coverage in the U.S.

Physician practices and attitudes regarding adult immunizations.

OBJECTIVES: To assess immunization practices and attitudes of U.S. primary care physicians regarding adult influenza and pneumococcal immunizations. METHODS: Mailed survey of primary care internists and family physicians across the United States; four follow-up contacts by mail and telephone. Bivariate and multivariate analyses assessed immunization practices and attitudes and differences by physician characteristics. RESULTS: Three hundred and sixteen of 668 eligible physicians responded (50 refused, response rate of 266 = 40%); 220 provided adult vaccinations. More than 64% indicated they routinely vaccinated patients >/=65 years and those <65 years with chronic disease indications with both influenza and pneumococcal vaccine. Reported barriers for influenza vaccination included vaccine safety concerns by patients (58%), urgent concerns dominating visits (43%), and inadequate reimbursement (26%). Reported barriers for pneumococcal vaccination included urgent concerns during office visits (44%), no patient immunization history (36%), patient concerns about vaccine safety (31%), and inadequate reimbursement (25%). Many physicians indicated willingness to try tracking systems (72%), chart reminders (55%), patient reminders (53%), standing orders (36%), external lists of unimmunized patients for pneumococcal vaccination (74%), external patient reminders (70%), and office training of physicians (36%) or staff (46%). CONCLUSIONS: While most physicians favored adult vaccinations, practical barriers to vaccination exist. Most physicians would adopt evidence-based strategies to improve immunization delivery.