Impact of cultural tightness on vaccination rate.

We find that cultural tightness, that is, the level of social punishment for violating norms, is associated with lower vaccination rates against COVID-19 across both states and counties in the United States. This is consistent with individuals in tighter cultures being more likely to base risk management decisions on social norms rather than on advice from experts and leaders. It is also consistent with our documentation of a social norm against COVID-19 vaccination. This implies that when a society depends on individual action to help manage society-wide risks, social norms can influence the degree to which individuals in tighter societies will engage in actions that minimize the overall risk to the society.

Role of Differences in Respiratory Syncytial Virus F and G Glycoproteins on Susceptibility to Inactivation by Antimicrobial Peptides LL-37 and Human Beta-Defensins.

Antimicrobial peptides are proteins that have been found to be an important factor in the natural immune response to a variety of pathogens. Respiratory syncytial virus (RSV) is a respiratory pathogen with the capability to cause serious upper and lower respiratory infections in infants and children and is a major viral cause of infant mortality. There is currently no functional vaccine for the virus, as recent efforts have been hindered by the virus's low immunogenicity, its ability to effectively mutate, and underlying instabilities of potential vaccines. Previous studies have shown that antimicrobial peptides may affect viral replication and spread of RSV. Our study evaluates the susceptibility of chimeric strains of RSV that express different fusion (F) and attachment (G) proteins to susceptibilities to inactivation by LL-37 and human beta-defensins (hBDs) hBD-1, hBD-3, and hBD-4. We show that LL-37 and hBD-3 result in dose-dependent, strain-independent inactivation of RSV, whereas treatment with either hBD-1 or hBD-4 appears more variable between strains. This suggests a potential role of the viral structural proteins in mitigating the inhibitory effects of the peptides. This study provides the first evidence of the sensitivity of RSV to several hBDs and indicates a role of LL-37 and beta-defensins in both limiting establishment of natural RSV infections and in the therapeutic treatment of severe RSV disease.

Phosphoethanolamine Transferase LptA in Haemophilus ducreyi Modifies Lipid A and Contributes to Human Defensin Resistance In Vitro.

Haemophilus ducreyi resists the cytotoxic effects of human antimicrobial peptides (APs), including α-defensins, ß-defensins, and the cathelicidin LL-37. Resistance to LL-37, mediated by the sensitive to antimicrobial peptide (Sap) transporter, is required for H. ducreyi virulence in humans. Cationic APs are attracted to the negatively charged bacterial cell surface. In other gram-negative bacteria, modification of lipopolysaccharide or lipooligosaccharide (LOS) by the addition of positively charged moieties, such as phosphoethanolamine (PEA), confers AP resistance by means of electrostatic repulsion. H. ducreyi LOS has PEA modifications at two sites, and we identified three genes (lptA, ptdA, and ptdB) in H. ducreyi with homology to a family of bacterial PEA transferases. We generated non-polar, unmarked mutants with deletions in one, two, or all three putative PEA transferase genes. The triple mutant was significantly more susceptible to both α- and ß-defensins; complementation of all three genes restored parental levels of AP resistance. Deletion of all three PEA transferase genes also resulted in a significant increase in the negativity of the mutant cell surface. Mass spectrometric analysis revealed that LptA was required for PEA modification of lipid A; PtdA and PtdB did not affect PEA modification of LOS. In human inoculation experiments, the triple mutant was as virulent as its parent strain. While this is the first identified mechanism of resistance to α-defensins in H. ducreyi, our in vivo data suggest that resistance to cathelicidin LL-37 may be more important than defensin resistance to H. ducreyi pathogenesis.

Deletion of mtrC in Haemophilus ducreyi increases sensitivity to human antimicrobial peptides and activates the CpxRA regulon.

Haemophilus ducreyi resists killing by antimicrobial peptides encountered during human infection, including cathelicidin LL-37, α-defensins, and ß-defensins. In this study, we examined the role of the proton motive force-dependent multiple transferable resistance (MTR) transporter in antimicrobial peptide resistance in H. ducreyi. We found a proton motive force-dependent effect on H. ducreyi's resistance to LL-37 and ß-defensin HBD-3, but not α-defensin HNP-2. Deletion of the membrane fusion protein MtrC rendered H. ducreyi more sensitive to LL-37 and human ß-defensins but had relatively little effect on α-defensin resistance. The mtrC mutant 35000HPmtrC exhibited phenotypic changes in outer membrane protein profiles, colony morphology, and serum sensitivity, which were restored to wild type by trans-complementation with mtrC. Similar phenotypes were reported in a cpxA mutant; activation of the two-component CpxRA regulator was confirmed by showing transcriptional effects on CpxRA-regulated genes in 35000HPmtrC. A cpxR mutant had wild-type levels of antimicrobial peptide resistance; a cpxA mutation had little effect on defensin resistance but led to increased sensitivity to LL-37. 35000HPmtrC was more sensitive than the cpxA mutant to LL-37, indicating that MTR contributed to LL-37 resistance independent of the CpxRA regulon. The CpxRA regulon did not affect proton motive force-dependent antimicrobial peptide resistance; however, 35000HPmtrC had lost proton motive force-dependent peptide resistance, suggesting that the MTR transporter promotes proton motive force-dependent resistance to LL-37 and human ß-defensins. This is the first report of a ß-defensin resistance mechanism in H. ducreyi and shows that LL-37 resistance in H. ducreyi is multifactorial.

Minimal clinically important differences of the childhood health assessment questionnaire.

OBJECTIVE: The Childhood Health Assessment Questionnaire (CHAQ) is a commonly used measure of disability and physical function for children with juvenile rheumatoid arthritis (JRA), whose scores range between 0 (no disability) and 3 (very severe disability), with a smallest potential difference in the CHAQ score of individuals at 0.125. We estimated minimal clinically important differences (MCID) of the CHAQ for worsening and improvement that were actually experienced by children with JRA using patient, parent, and clinical perspectives. METHODS: Changes in CHAQ scores were calculated for parent (n = 92) and patient ratings (children age > or = 8 yrs only; n = 67) between subsequent clinic visits. Changes in patient well being and disease activity and the occurrence of flare or important improvement between visits served as external standards for the MCID. MCID were defined as the median changes of the CHAQ scores of individual patients who had a minimal important improvement or worsening between visits. RESULTS: The median change in CHAQ scores of patients who rated themselves or were rated by others as unchanged was often 0. Depending on the external standard used, the MCID for improvement of the CHAQ was -0.188 at most, while the MCID for worsening was at most +0.125. CONCLUSION: The MCID of the CHAQ for both improvement and worsening are often at or close to the level of the smallest potential difference, suggesting that the CHAQ is relatively insensitive to important short term changes in children with JRA. This may warrant a change in the calculation of the global CHAQ score, or the development of more sensitive functional measures.

Health of children with chronic arthritis: relationship of different measures and the quality of parent proxy reporting.

OBJECTIVE: To examine the strength of the association between different measures of health-related quality of life (HRQOL), disability, pain, and well-being in children with chronic arthritis. To evaluate whether HRQOL scores vary as a function of disability status beyond chance. To assess the quality of the parent proxy report for HRQOL as compared with disability, pain, and well-being. METHODS: Measures of HRQOL (visual analog scale [VAS] of health, Pediatric Quality of Life Inventory [PedsQL], Juvenile Arthritis Quality of Life Questionnaire (JAQQ), and modified standard gamble technique [SG]), disability (Childhood Health Assessment Questionnaire), VAS of pain, and VAS of well-being (VAS-well) were completed by the parents (n = 119) and patients > or =8 years (SG: > or =12 years). RESULTS: HRQOL was highest when measured by the SG, whose utilities were no more than weakly correlated with any of the other outcomes. The values of all other HRQOL measures were at least moderately correlated with each other and with the VAS-well. Irrespective of the measure used, disability was associated with significantly decreased HRQOL. There was fair to good agreement and moderate consistency of the HRQOL ratings (SG: fair consistency) between patients and parents with marked differences between health domains. CONCLUSION: HRQOL measured by the PedsQL, JAQQ, and VAS are moderately to highly correlated with each other in children with chronic arthritis. The children's HRQOL significantly decreases with increasing disability. Despite more pronounced differences for some health domains, parents are moderate to good proxy reporters of HRQOL, disability, and well-being of children with chronic arthritis.