Social Stigma and COVID-19 Vaccine Refusal in France.

CONTEXT: In 2021, French health authorities strongly promoted the vaccination against Covid-19. We assumed that refusing this vaccine became a 'stigma', and we investigated potential 'public stigma' toward unvaccinated people among the French population. METHODS: A representative sample of the French adult population (N = 2,015) completed an online questionnaire in September 2021. We focused on participants who were already vaccinated against Covid-19, or intended to get vaccinated (N = 1,742). A cluster analysis was used to obtain contrasted attitudinal profiles, and we investigated associated factors with logistic regressions. FINDINGS: Regarding attitudes toward unvaccinated people, several pejorative statements were supported by a majority of respondents, and a significant minority also endorsed social rejection attitudes. We found four contrasted attitudinal profiles: Moral condemnation only (32% of respondents), Full stigma (26%), No stigma (26%) and Stigma rejection (16%). Early vaccination, civic motives for it, faith in science, rejection of political extremes and being 65 or over were the main factors of stigmatizing attitudes toward unvaccinated people. CONCLUSIONS: We found some evidence of stigmatization toward unvaccinated people, but further research is needed, especially to investigate perceived stigmatization among them. We discussed our results in reference with the concept of 'Folk Devils', and from a public health perspective.

Explaining Political Differences in Attitudes to Vaccines in France: Partisan Cues, Disenchantment with Politics and Political Sophistication.

CONTEXT: The role of political identities in determining attitudes to vaccines has attracted a lot of attention in the last decade. Explanations have tended to focus on the influence of party representatives on their sympathizers (partisan cues). METHODS: Four representatives samples of the French adult population completed online questionnaires between July 2021 and May 2022 (N = 9,177). Bivariate and multivariate analyses were performed to test whether partisan differences in attitudes to vaccines are best explained by partisan cues or by parties' differences in propensity to attract people who distrust the actors involved in vaccination policies. FINDINGS: People who feel close to parties at the far left, the far right and to green parties are more vaccine hesitant. We found a small evidence for the effect of partisan cues and a much stronger effect of trust. But more importantly, we show that the more politically sophisticated are less vaccine hesitant and that the non-partisan are the biggest and most vaccine-hesitant group. CONCLUSIONS: The literature has focused on the case of the USA but turning the attention towards countries where disenchantment with politics is more marked helps better understand the different ways trust, partisanship and political sophistication can affect attitudes to vaccines.

Entre santé et science : littératie en santé et perception de la recherche médicale.

OBJECTIVE: Biomedical innovation plays an important role in health care pathways and public debates. Nevertheless, existing measures of health literacy take little account of medical research. In this article, we explore the relationship between health literacy and attitudes toward medical research, from clinical trials to more general attitudes toward science. METHODS: We analyze the results of two self-administered questionnaires conducted on samples of the French adult population in 2020 and 2021 (N=2003 and N=2022). A series of twelve questions assessed health literacy (HLS19-Q12-EN) and ten questions addressed attitudes to clinical trials, medical research, and science in general. The analyses characterize the population’s perception of medical research issues and its association with health literacy. RESULTS: There is a significant association between health literacy and perception of research. A low level of literacy is associated with lower knowledge of clinical trials and a more negative attitude toward them, less confidence in science and its contributions to society. CONCLUSIONS: Given the continuity between care and research, health literacy is likely to be a relevant measure for characterizing disparity in attitudes toward clinical trials and improving access to innovation.

Vaccine hesitancy about the HPV vaccine among French young women and their parents: a telephone survey.

BACKGROUND: The human papillomavirus (HPV) vaccine reduces the burden of cervical and other cancers. In numerous countries, a slow uptakeof this vaccine persists, calling for a better understanding of the structural factors leading to vaccine acceptation. We aimed to assess the attitudes toward HPV vaccination among its intended public to explore its specific characteristics. METHODS: A random cross-sectional telephone survey of the French general population provided data from a sample of 2426 respondents of the target public: the parents of young women and the young women aged 15-25 themselves. We applied cluster analysis to identify contrasting attitudinal profiles, and logistic regressions with a model averaging method to investigate and rank the factors associated with these profiles. RESULTS: A third of the respondents had never heard of HPV. However, most of the respondents who had heard of it agreed that it is a severe (93.8%) and frequent (65.1%) infection. Overall, 72.3% of them considered the HPV vaccine to be effective, but 54% had concerns about its side effects. We identified four contrasting profiles based on their perceptions of this vaccine: informed supporters, objectors, uninformed supporters, and those who were uncertain. In multivariate analysis, these attitudinal clusters were the strongest predictors of HPV vaccine uptake, followed by attitudes toward vaccination in general. CONCLUSIONS: Tailored information campaigns and programs should address the specific and contrasted concerns about HPV vaccination of both young women and of their parents.

Topical therapy with negative allosteric modulators of the calcium-sensing receptor (calcilytics) for the management of asthma: the beginning of a new era?

In this review article we present the evidence to date supporting the role of the calcium-sensing receptor (CaSR) as a key, pluripotential molecular trigger for asthma and speculate on the likely benefits of topical therapy of asthma with negative allosteric modulators of the CaSR: calcilytics.

Factors associated with COVID-19 vaccine uptake among French population aged 65 years and older: results from a national online survey.

BACKGROUND: In France, the increase in COVID-19 vaccine uptake among older adults slowed down between May and June 2021. Using the data from a national survey, we aimed to assess COVID-19 vaccine uptake among French residents aged 65 years and older, particularly at risk of severe form of the infection, and identify factors associated with non-vaccination. METHODS: A cross-sectional online survey collected the immunization status/intention to get the COVID-19 vaccine, reasons for vaccination/non-vaccination and factors potentially associated with vaccine uptake between May 10 and 23, 2021 among a large sample of French residents. Characteristics of participants were compared according to immunization status. Factors potentially associated with non-vaccination were computed into a multivariate logistic regression. RESULTS: Among the 1941 survey participants, 1612 (83%) reported having received at least one dose of COVID-19 vaccine. Among the 329 unvaccinated, 197 (60%) declared having the intention to get vaccinated. Younger age (adjusted odds ratio (aOR) = 1.50; 95% confidence interval (CI), 1.05-2.14), thinking previously having COVID-19 (aOR = 4.01; 95% CI, 2.17-7.40), having suffered economic impact due to the pandemic (aOR = 2.63; 95% CI, 1.71-4.04), reporting an "unsafe" opinion about COVID-19 vaccine safety (aOR = 6.79; 95% CI, 4.50-10.26), reporting an "unsupportive" opinion about vaccination in general (aOR = 4.24; 95% CI, 2.77-6.49) were independent risk factors for non-vaccination. On the other hand, trust in COVID-19 vaccine information delivered by the doctor (aOR = 0.28; 95% CI, 0.16-0.48) and trust in the government's actions (aOR = 0.50; 95% CI, 0.34-0.74) were independent protective factors for non-vaccination. Political affiliation also remained significantly associated with vaccine uptake. CONCLUSIONS: Despite high overall COVID-19 vaccine uptake among the study participants, differences in vaccine uptake according to the level of concerns regarding COVID-19 vaccine safety, socioeconomic profile and trust in the government were observed. Our results reinforce the importance of "reaching out" vaccination strategy that specifically targets the most vulnerable fringe of older adult population.

From contact tracing to COVID-19 pass holder; the tortured journey of the French TousAntiCovid contact tracing app.

OBJECTIVES: Our study aimed to provide an updated overview of the use of the French contact tracing application, TousAntiCovid, and identify evolutions since the beginning of the pandemic. STUDY DESIGN: We conducted a survey study on a representative sample of the French adult population. METHODS: Our data were collected by the Obervatoire Régional de la Santé (ORS) using a self-administered online questionnaire. This was completed by a sample of 2,022 people stratified to match French official census statistics for gender, age, occupation, and area of housing. We conducted statistical analysis using Python (Pandas - Scipy - Statsmodels) with chi-squared and Wilcoxon rank-sum tests to control for statistical significance. RESULTS: A small majority of respondents used TousAntiCovid (55.5%), while 41.0% had never downloaded it. Only one-quarter of the respondents (23.3%) used it for contact tracing with Bluetooth, while a third (32.2%) used it only for storing their health pass. The app's use increased with education level, income, and younger age. A large majority (85%) of non-vaccinated respondents had never downloaded TousAntiCovid. CONCLUSION: Our results suggest that the role and use of France's official COVID-19 app TousAntiCovid has evolved in line with the government's strategy; while initially focusing on contact tracing, its development has led to the possibility to store test and vaccination documentation. The survey also confirmed previous results pointing to the lasting differences in socio-economic status in terms of adoption of the app. This is problematic because the long-term nature of the pandemic could require the government to keep a range of strategies open, including contact tracing. Public discussion of the current and future roles of the French contact tracing app is therefore needed.

Attitudes about COVID-19 Lockdown among General Population, France, March 2020.

Because the effectiveness of a coronavirus disease lockdown in curbing coronavirus disease spread depends on public support, acquiring real-time information about the way populations reacted to the lockdown is crucial. In France, such public support remained fragile among low-income persons, probably because the lockdown exacerbated preexisting social inequalities and conflicts.

Indeterminate QuantiFERON Gold Plus Results Reveal Deficient Interferon Gamma Responses in Severely Ill COVID-19 Patients.

SARS-CoV-2 is a novel positive-sense single-stranded RNA virus that has caused a recent pandemic. Most patients have a mild disease course, while approximately 20% have moderate to severe disease, often requiring hospitalization and, in some cases, care in the intensive care unit. By investigating a perceived increased rate of indeterminate QuantiFERON-TB Gold Plus results in hospitalized COVID patients, we demonstrate that severely ill COVID-19 patients have at least a 6-fold reduction of interferon gamma (IFN-γ) levels compared to control patients. What is more, over 60% of these severely ill COVID-19 patients' peripheral T cells were found to be unable to produce measurable IFN-γ when stimulated with phytohemagglutinin (PHA), a potent IFN-γ mitogen, reflected by an indeterminate QuantiFERON-TB Gold Plus result. This defect of IFN-γ production was independent of absolute lymphocyte counts and immunosuppressive therapy. It was associated with increased levels of interleukin-6 (IL-6), which was a predictor of patient outcomes for our cohort when measured early in the course of disease. Finally, in a subset of COVID-19 patients, we found elevated IL-10 levels in addition to IL-6 elevation. In addition to finding a significant limitation of interferon-gamma release assay (IGRA) testing in severely ill COVID-19 patients, these data provide evidence that many of these patients demonstrate a focused Th2 immune response with inhibition of IFN-γ signaling and, in many cases, significant elevations of IL-6.

Characterization of Negative Allosteric Modulators of the Calcium-Sensing Receptor for Repurposing as a Treatment of Asthma.

Asthma is still an incurable disease, and there is a recognized need for novel small-molecule therapies for people with asthma, especially those poorly controlled by current treatments. We previously demonstrated that calcium-sensing receptor (CaSR) negative allosteric modulators (NAMs), calcilytics, uniquely suppress both airway hyperresponsiveness (AHR) and inflammation in human cells and murine asthma surrogates. Here we assess the feasibility of repurposing four CaSR NAMs, which were originally developed for oral therapy for osteoporosis and previously tested in the clinic as a novel, single, and comprehensive topical antiasthma therapy. We address the hypotheses, using murine asthma surrogates, that topically delivered CaSR NAMs 1) abolish AHR; 2) are unlikely to cause unwanted systemic effects; 3) are suitable for topical application; and 4) inhibit airway inflammation to the same degree as the current standard of care, inhaled corticosteroids, and, furthermore, inhibit airway remodeling. All four CaSR NAMs inhibited poly-L-arginine-induced AHR in naïve mice and suppressed both AHR and airway inflammation in a murine surrogate of acute asthma, confirming class specificity. Repeated exposure to inhaled CaSR NAMs did not alter blood pressure, heart rate, or serum calcium concentrations. Optimal candidates for repurposing were identified based on anti-AHR/inflammatory activities, pharmacokinetics/pharmacodynamics, formulation, and micronization studies. Whereas both inhaled CaSR NAMs and inhaled corticosteroids reduced airways inflammation, only the former prevented goblet cell hyperplasia in a chronic asthma model. We conclude that inhaled CaSR NAMs are likely a single, safe, and effective topical therapy for human asthma, abolishing AHR, suppressing airways inflammation, and abrogating some features of airway remodeling. SIGNIFICANCE STATEMENT: Calcium-sensing receptor (CaSR) negative allosteric modulators (NAMs) reduce airway smooth muscle hyperresponsiveness, reverse airway inflammation as efficiently as topical corticosteroids, and suppress airway remodeling in asthma surrogates. CaSR NAMs, which were initially developed for oral therapy of osteoporosis proved inefficacious for this indication despite being safe and well tolerated. Here we show that structurally unrelated CaSR NAMs are suitable for inhaled delivery and represent a one-stop, steroid-free approach to asthma control and prophylaxis.

Vaccine Hesitancy, Acceptance, and Anti-Vaccination: Trends and Future Prospects for Public Health.

An often-stated public health comment is that "vaccination is a victim of its own success." While the scientific and medical consensus on the benefits of vaccination is clear and unambiguous, an increasing number of people are perceiving vaccines as unsafe and unnecessary. The World Health Organization identified "the reluctance or refusal to vaccinate despite availability of vaccines" as one of the 10 threats to global health in 2019. The negative influence of anti-vaccination movements is often named as a cause of increasing vaccine resistance in the public. In this review, we give an overview of the current literature on the topic, beginning by agreeing on terminology and concepts before looking at potential causes, consequences, and impacts of resistance to vaccination.

The hydroxychloroquine debate: a therapeutic dilemma for general practitioners.

France has been at the epicenter of the worldwide debate about hydroxychloroquine, as the main advocacy for its use to treat COVID-19 comes from a research unit led by Didier Raoult in Marseille. Among a national panel of 2940 general practitioners, we found that physicians in the areas most strongly affected by the epidemic or closest to the epicenter of the controversy reported that the hydroxychloroquine debate had made it difficult for them to deal with patients' treatment requests. Their adherence to official recommendations was also lower. It will be necessary to examine the conditions producing so strong a conflict.

Diplorickettsia Bacteria in an Ixodes scapularis Tick, Vermont, USA.

An unexpected Diplorickettsia species closely related to the tickborne pathogen D. massieliensis was found in the microbiome of an Ixodes scapularis tick in Vermont, USA. This evidence of Diplorickettsia in North American ticks suggests a need for disease surveillance using molecular screening of ticks and serologic studies of humans.

The Impact of a Laparoscopic Surgery Training Course in a Developing Country.

INTRODUCTION: Surgeons training junior colleagues to perform laparoscopic surgery find the 'apprenticeship' model of surgical training inadequate. Therefore, the use of training courses involving simulation have become an important way to teach laparoscopic surgery. An annual laparoscopic surgery course began in Nepal in 2013. It is difficult to assess the impact of the course on trainees and demonstrate a subsequent improvement in patient outcomes, but one way is to ask delegates for reflections on their experience of the course and their perception of how it has impacted patients. METHODS: The course involved simulation and patient-based training. A questionnaire to collect quantitative data and qualitative comments was sent to all 80 previous delegates (at least 9 months after the course) in September 2018. RESULTS: Twenty-eight delegates responded. The majority demonstrated career progression since completing the course (independent practitioners increased from 7 to 50%) and progression in their practice (18% had performed >20 laparoscopic procedures at the time of the course, vs 70% at the time of the questionnaire). All delegates felt that laparoscopic training is useful in the Nepalese context. Delegates felt the course was useful in developing skills, and improving confidence and safety. Suggestions for improvement included lengthening the course and increasing the amount of practical exposure. CONCLUSION: There was a positive outcome of the course to Kirkpatrick level 2. There is a need to expand the course's scope to an advanced level, increase its length and start courses in other centres, to ensure the most possible benefit to patients.

Hypoxic pulmonary vasoconstriction.

It has been known for more than 60 years, and suspected for over 100, that alveolar hypoxia causes pulmonary vasoconstriction by means of mechanisms local to the lung. For the last 20 years, it has been clear that the essential sensor, transduction, and effector mechanisms responsible for hypoxic pulmonary vasoconstriction (HPV) reside in the pulmonary arterial smooth muscle cell. The main focus of this review is the cellular and molecular work performed to clarify these intrinsic mechanisms and to determine how they are facilitated and inhibited by the extrinsic influences of other cells. Because the interaction of intrinsic and extrinsic mechanisms is likely to shape expression of HPV in vivo, we relate results obtained in cells to HPV in more intact preparations, such as intact and isolated lungs and isolated pulmonary vessels. Finally, we evaluate evidence regarding the contribution of HPV to the physiological and pathophysiological processes involved in the transition from fetal to neonatal life, pulmonary gas exchange, high-altitude pulmonary edema, and pulmonary hypertension. Although understanding of HPV has advanced significantly, major areas of ignorance and uncertainty await resolution.

'I Think I Made The Right Decision I Hope I'm Not Wrong'. Vaccine hesitancy, commitment and trust among parents of young children.

During the last decade, public health research has emphasised the growing public disaffection with vaccination. This contemporary vaccine hesitation (VH) refers to a delay in acceptance or refusal of vaccines, as well as agreement despite doubt and reluctance. We investigated VH among French parents of young children, with an emphasis on two key features of VH: trust towards physicians and commitment to vaccination issues. We targeted two populations with contrasting socioeconomic profiles, using in-depth interviews (n = 25). Most parents exhibited some kind of VH, with differentiated attitudes across vaccines, including acceptance despite enduring doubts, especially for vaccines already provided to older siblings ('vaccine inertia'). Despite the rise of the Internet and social media, our participants still strongly relied on face-to-face interactions with peers and significant others. Most participants trusted their own physician but this was the result of a selection process: they had engaged resources to find a physician they could trust. Participants with contrasted socioeconomic profiles struggled with the same dilemmas, and they committed themselves to the same quest to find the 'right' physician. Nevertheless, parents with a higher socioeconomic status were able to engage more resources and use a wider repertoire of actions, and they also displayed greater health literacy.

The Density of the Lyme Disease Vector, Ixodes scapularis (Blacklegged Tick), Differs Between the Champlain Valley and Green Mountains, Vermont.

Lyme disease is an emerging infectious disease of public health concern in the northeastern United States. The disease's vector, Ixodes scapularis (Say) (Blacklegged Tick), has increased its range in the past twenty years. In its newly endemic northern range there have been few studies of the Blacklegged Tick's habitat associations. From 2016-2018, we sampled for nymphal Blacklegged Ticks in the Champlain Valley and Green Mountains of Addison County, Vermont, and tested them for Borrelia burgdorferi, the Lyme disease agent. We found 10 times more ticks in the Champlain Valley than in the Green Mountains. Nymphal infection prevalence was 0.21 and did not vary by year or region. The difference in tick density reported has public health consequences, as Vermont has one of the highest rates of Lyme disease in the United States.

Transforming growth factor-ß enhances Rho-kinase activity and contraction in airway smooth muscle via the nucleotide exchange factor ARHGEF1.

KEY POINTS: Transforming growth-factor-ß (TGF-ß) and RhoA/Rho-kinase are independently implicated in the airway hyper-responsiveness associated with asthma, but how these proteins interact is not fully understood. We examined the effects of pre-treatment with TGF-ß on expression and activity of RhoA, Rho-kinase and ARHGEF1, an activator of RhoA, as well as on bradykinin-induced contraction, in airway smooth muscle. TGF-ß enhanced bradykinin-induced RhoA translocation, Rho-kinase-dependent phosphorylation and contraction, but partially suppressed bradykinin-induced RhoA activity (RhoA-GTP content). TGF-ß enhanced the expression of ARHGEF1, while a small interfering RNA against ARHGEF1 and a RhoGEF inhibitor prevented the effects of TGF-ß on RhoA and Rho-kinase activity and contraction, respectively. ARHGEF1 expression was also enhanced in airway smooth muscle from asthmatic patients and ovalbumin-sensitized mice. ARHGEF1 is a key TGF-ß target gene, an important regulator of Rho-kinase activity and therefore a potential therapeutic target for the treatment of asthmatic airway hyper-responsiveness. ABSTRACT: Transforming growth factor-ß (TGF-ß), RhoA/Rho-kinase and Src-family kinases (SrcFK) have independently been implicated in airway hyper-responsiveness, but how they interact to regulate airway smooth muscle contractility is not fully understood. We found that TGF-ß pre-treatment enhanced acute contractile responses to bradykinin (BK) in isolated rat bronchioles, and inhibitors of RhoGEFs (Y16) and Rho-kinase (Y27632), but not the SrcFK inhibitor PP2, prevented this enhancement. In cultured human airway smooth muscle cells (hASMCs), TGF-ß pre-treatment enhanced the protein expression of the Rho guanine nucleotide exchange factor ARHGEF1, MLC20 , MYPT-1 and the actin-severing protein cofilin, but not of RhoA, ROCK2 or c-Src. In hASMCs, acute treatment with BK triggered subcellular translocation of ARHGEF1 and RhoA and enhanced auto-phosphorylation of SrcFK and phosphorylation of MYPT1 and MLC20 , but induced de-phosphorylation of cofilin. TGF-ß pre-treatment amplified the effects of BK on RhoA translocation and MYPT1/MLC20 phosphorylation, but suppressed the effects of BK on RhoA-GTP content, SrcFK auto-phosphorylation and cofilin de-phosphorylation. In hASMCs, an ARHGEF1 small interfering RNA suppressed the effects of BK and TGF-ß on RhoA-GTP content, RhoA translocation and MYPT1 and MLC20 phosphorylation, but minimally influenced the effects of TGF-ß on cofilin expression and phosphorylation. ARHGEF1 expression was also enhanced in ASMCs of asthmatic patients and in lungs of ovalbumin-sensitized mice. Our data indicate that TGF-ß enhances BK-induced contraction, RhoA translocation and Rho-kinase activity in airway smooth muscle largely via ARHGEF1, but independently of SrcFK and total RhoA-GTP content. A role for smooth muscle ARHGEF1 in asthmatic airway hyper-responsiveness is worthy of further investigation.

Role of reactive oxygen species and sulfide-quinone oxoreductase in hydrogen sulfide-induced contraction of rat pulmonary arteries.

Application of H2S ("sulfide") elicits a complex contraction in rat pulmonary arteries (PAs) comprising a small transient contraction (phase 1; Ph1) followed by relaxation and then a second, larger, and more sustained contraction (phase 2; Ph2). We investigated the mechanisms causing this response using isometric myography in rat second-order PAs, with Na2S as a sulfide donor. Both phases of contraction to 1,000 µM Na2S were attenuated by the pan-PKC inhibitor Gö6983 (3 µM) and by 50 µM ryanodine; the Ca2+ channel blocker nifedipine (1 µM) was without effect. Ph2 was attenuated by the mitochondrial complex III blocker myxothiazol (1 µM), the NADPH oxidase (NOX) blocker VAS2870 (10 µM), and the antioxidant TEMPOL (3 mM) but was unaffected by the complex I blocker rotenone (1 µM). The bath sulfide concentration, measured using an amperometric sensor, decreased rapidly following Na2S application, and the peak of Ph2 occurred when this had fallen to ~50 µM. Sulfide caused a transient increase in NAD(P)H autofluorescence, the offset of which coincided with development of the Ph2 contraction. Sulfide also caused a brief mitochondrial hyperpolarization (assessed using tetramethylrhodamine ethyl ester), followed immediately by depolarization and then a second more prolonged hyperpolarization, the onset of which was temporally correlated with the Ph2 contraction. Sulfide application to cultured PA smooth muscle cells increased reactive oxygen species (ROS) production (recorded using L012); this was absent when the mitochondrial flavoprotein sulfide-quinone oxoreductase (SQR) was knocked down using small interfering RNA. We propose that the Ph2 contraction is largely caused by SQR-mediated sulfide metabolism, which, by donating electrons to ubiquinone, increases electron production by complex III and thereby ROS production.