Why did Swiss citizens vote to ban tobacco advertising?

In February 2022, Swiss citizens agreed to modify the Swiss Constitution to ban tobacco advertising reaching children and adolescents. This case study analyses the arguments used by both opponents and supporters of the constitutional amendment. Opponents argued that the proposed regulation went too far, threatened the economy, restricted personal freedom, was superfluous as the current law already protected youth and that it opened the door to marketing bans of other harmful products. Proponents focused on youth protection and invoked the burden of smoking on public health and the fact that advertising bans are an effective evidence-based measure. A comparison with previous campaigns to ban tobacco advertising that had failed suggests factors accounting for the positive vote in 2022. These include the strategic framing of youth protection, the separation of tobacco from other issues (such as alcohol advertising), the deteriorating image of the tobacco industry and the ability of the proponents to mobilise a broad coalition of health and youth organisations, with improved funding and communication. The lessons may be instructive for other campaigns seeking to regulate commercial determinants of health.

[New puff-like disposable electronic cigarettes: expert consensus on their regulation]. / Nouvelles cigarettes électroniques jetables « puffs ¼ : consensus d'expert-e-s sur leur réglementation.

New disposable electronic cigarettes have arrived on the Swiss market since 2020. Our study, conducted according to the three steps of the Delphi fast-track approach developed at Unisanté, obtained a consensual agreement among French-speaking Switzerland experts on the regulation of these products. Ideally, the panel of experts recommends a sales ban of the product. If this is not possible, a number of aspects should be strictly regulated: taxation, product composition and marketing, and sales and consumption restrictions. These regulations should go further than the current European directive and the future Swiss law. The conclusions will be useful to support and guide political decision making from a public health and environmental perspective.

De nouvelles cigarettes électroniques jetables sont arrivées sur le marché suisse depuis 2020. Notre étude, conduite selon les trois étapes de la démarche Delphi fast-track développée à Unisanté, a obtenu un accord consensuel entre expert-e-s suisses romand-e-s sur la réglementation de ces produits. Dans l'idéal, le panel d'expert-e-s recommande une interdiction de vente du produit. Si cela n'est pas possible, certains aspects doivent être strictement réglementés : taxation, composition des produits et marketing, restrictions de vente et de consommation. Ces réglementations devraient aller plus loin que l'actuelle directive européenne et la future loi suisse. Les conclusions seront utiles pour soutenir et orienter la prise de décision politique dans une perspective de santé publique et environnementale.

Acetate, a metabolic product of Heligmosomoides polygyrus, facilitates intestinal epithelial barrier breakdown in a FFAR2-dependent manner.

Approximately 2 billion people worldwide and a significant part of the domestic livestock are infected with soil-transmitted helminths, of which many establish chronic infections causing substantial economic and welfare burdens. Beside intensive research on helminth-triggered mucosal and systemic immune responses, the local mechanism that enables infective larvae to cross the intestinal epithelial barrier and invade mucosal tissue remains poorly addressed. Here, we show that Heligmosomoides polygyrus infective L3s secrete acetate and that acetate potentially facilitates paracellular epithelial tissue invasion by changed epithelial tight junction claudin expression. In vitro, impedance-based real-time epithelial cell line barrier measurements together with ex vivo functional permeability assays in intestinal organoid cultures revealed that acetate decreased intercellular barrier function via the G-protein coupled free fatty acid receptor 2 (FFAR2, GPR43). In vivo validation experiments in FFAR2-/- mice showed lower H. polygyrus burdens, whereas oral acetate-treated C57BL/6 wild type mice showed higher burdens. These data suggest that locally secreted acetate - as a metabolic product of the energy metabolism of H. polygyrus L3s - provides a significant advantage to the parasite in crossing the intestinal epithelial barrier and invading mucosal tissues. This is the first and a rate-limiting step for helminths to establish chronic infections in their hosts and if modulated could have profound consequences for their life cycle.

Microbial regulation of intestinal motility provides resistance against helminth infection.

Soil-transmitted helminths cause widespread disease, infecting ~1.5 billion people living within poverty-stricken regions of tropical and subtropical countries. As adult worms inhabit the intestine alongside bacterial communities, we determined whether the bacterial microbiota impacted on host resistance against intestinal helminth infection. We infected germ-free, antibiotic-treated and specific pathogen-free mice, with the intestinal helminth Heligmosomoides polygyrus bakeri. Mice harboured increased parasite numbers in the absence of a bacterial microbiota, despite mounting a robust helminth-induced type 2 immune response. Alterations to parasite behaviour could already be observed at early time points following infection, including more proximal distribution of infective larvae along the intestinal tract and increased migration in a Baermann assay. Mice lacking a complex bacterial microbiota exhibited reduced levels of intestinal acetylcholine, a major excitatory intestinal neurotransmitter that promotes intestinal transit by activating muscarinic receptors. Both intestinal motility and host resistance against larval infection were restored by treatment with the muscarinic agonist bethanechol. These data provide evidence that a complex bacterial microbiota provides the host with resistance against intestinal helminths via its ability to regulate intestinal motility.

Infection with a small intestinal helminth, Heligmosomoides polygyrus bakeri, consistently alters microbial communities throughout the murine small and large intestine.

Increasing evidence suggests that intestinal helminth infection can alter intestinal microbial communities with important impacts on the mammalian host. However, all of the studies to date utilize different techniques to study the microbiome and access different sites of the intestine with little consistency noted between studies. In the present study, we set out to perform a comprehensive analysis of the impact of intestinal helminth infection on the mammalian intestinal bacterial microbiome. For this purpose, we investigated the impact of experimental infection using the natural murine small intestinal helminth, Heligmosomoides polygyrus bakeri and examined possible alterations in both the mucous and luminal bacterial communities along the entire small and large intestine. We also explored the impact of common experimental variables including the parasite batch and pre-infection microbiome, on the outcome of helminth-bacterial interactions. This work provides evidence that helminth infection reproducibly alters intestinal microbial communities, with an impact of infection noted along the entire length of the intestine. Although the exact nature of helminth-induced alterations to the intestinal microbiome differed depending on the microbiome community structure present prior to infection, changes extended well beyond the introduction of new bacterial species by the infecting larvae. Moreover, striking similarities between different experiments were noted, including the consistent outgrowth of a bacterium belonging to the Peptostreptococcaceae family throughout the intestine.

Lymphotoxin-Dependent B Cell-FRC Crosstalk Promotes De Novo Follicle Formation and Antibody Production following Intestinal Helminth Infection.

Secondary lymphoid tissues provide specialized niches for the initiation of adaptive immune responses and undergo a remarkable expansion in response to inflammatory stimuli. Although the formation of B cell follicles was previously thought to be restricted to the postnatal period, we observed that the draining mesenteric lymph nodes (mLN) of helminth-infected mice form an extensive number of new, centrally located, B cell follicles in response to IL-4Rα-dependent inflammation. IL-4Rα signaling promoted LTα1ß2 (lymphotoxin) expression by B cells, which then interacted with CCL19 positive stromal cells to promote lymphoid enlargement and the formation of germinal center containing B cell follicles. Importantly, de novo follicle formation functioned to promote both total and parasite-specific antibody production. These data reveal a role for type 2 inflammation in promoting stromal cell remodeling and de novo follicle formation by promoting B cell-stromal cell crosstalk.

Vaccination with LAG-3Ig (IMP321) and Peptides Induces Specific CD4 and CD8 T-Cell Responses in Metastatic Melanoma Patients--Report of a Phase I/IIa Clinical Trial.

PURPOSE: Cancer vaccines aim to generate and maintain antitumor immune responses. We designed a phase I/IIa clinical trial to test a vaccine formulation composed of Montanide ISA-51 (Incomplete Freund's Adjuvant), LAG-3Ig (IMP321, a non-Toll like Receptor agonist with adjuvant properties), and five synthetic peptides derived from tumor-associated antigens (four short 9/10-mers targeting CD8 T-cells, and one longer 15-mer targeting CD4 T-cells). Primary endpoints were safety and T-cell responses. EXPERIMENTAL DESIGN: Sixteen metastatic melanoma patients received serial vaccinations. Up to nine injections were subcutaneously administered in three cycles, each with three vaccinations every 3 weeks, with 6 to 14 weeks interval between cycles. Blood samples were collected at baseline, 1-week after the third, sixth and ninth vaccination, and 6 months after the last vaccination. Circulating T-cells were monitored by tetramer staining directly ex vivo, and by combinatorial tetramer and cytokine staining on in vitro stimulated cells. RESULTS: Side effects were mild to moderate, comparable to vaccines with Montanide alone. Specific CD8 T-cell responses to at least one peptide formulated in the vaccine preparation were found in 13 of 16 patients. However, two of the four short peptides of the vaccine formulation did not elicit CD8 T-cell responses. Specific CD4 T-cell responses were found in all 16 patients. CONCLUSIONS: We conclude that vaccination with IMP321 is a promising and safe strategy for inducing sustained immune responses, encouraging further development for cancer vaccines as components of combination therapies.

The Intestinal Microbiota Contributes to the Ability of Helminths to Modulate Allergic Inflammation.

Intestinal helminths are potent regulators of their host's immune system and can ameliorate inflammatory diseases such as allergic asthma. In the present study we have assessed whether this anti-inflammatory activity was purely intrinsic to helminths, or whether it also involved crosstalk with the local microbiota. We report that chronic infection with the murine helminth Heligmosomoides polygyrus bakeri (Hpb) altered the intestinal habitat, allowing increased short chain fatty acid (SCFA) production. Transfer of the Hpb-modified microbiota alone was sufficient to mediate protection against allergic asthma. The helminth-induced anti-inflammatory cytokine secretion and regulatory T cell suppressor activity that mediated the protection required the G protein-coupled receptor (GPR)-41. A similar alteration in the metabolic potential of intestinal bacterial communities was observed with diverse parasitic and host species, suggesting that this represents an evolutionary conserved mechanism of host-microbe-helminth interactions.

Parasite Proximity Drives the Expansion of Regulatory T Cells in Peyer's Patches following Intestinal Helminth Infection.

Helminth infections are typically chronic in nature; however, the exact molecular mechanisms by which these parasites promote or thwart host immunity remain unclear. Worm expulsion requires the differentiation of CD4(+) T cells into Th2 cells, while regulatory T cells (Tregs) act to dampen the extent of the Th2 response. Priming of T cells requires drainage or capture of antigens within lymphoid tissues, and in the case of intestinal helminths, such sites include the mucosa-associated Peyer's patches (PPs) and the draining mesenteric lymph nodes (MLN). To gain insight into when and where the activation of the adaptive T cell response takes place following intestinal helminth infection, we analyzed Th2 and Treg responses in the PPs and MLN following infection with the murine intestinal helminth Heligmosomoides polygyrus bakeri. Protective Th2 responses were observed to be largely restricted to the MLN, while a greater expansion of Tregs occurred within the PPs. Interestingly, those PPs that formed a contact with the parasite showed the greatest degree of Treg expansion and no evidence of type 2 cytokine production, indicating that the parasite may secrete products that act in a local manner to selectively promote Treg expansion. This view was supported by the finding that H. polygyrus bakeri larvae could promote Treg proliferation in vitro. Taken together, these data indicate that different degrees of Treg expansion and type 2 cytokine production occur within the PPs and MLN following infection with the intestinal helminth H. polygyrus bakeri and indicate that these organs exhibit differential responses following infection with intestinal helminths.

Stoichiometry of Heteromeric BAFF and APRIL Cytokines Dictates Their Receptor Binding and Signaling Properties.

The closely related TNF family ligands B cell activation factor (BAFF) and a proliferation-inducing ligand (APRIL) serve in the generation and maintenance of mature B-lymphocytes. Both BAFF and APRIL assemble as homotrimers that bind and activate several receptors that they partially share. However, heteromers of BAFF and APRIL that occur in patients with autoimmune diseases are incompletely characterized. The N and C termini of adjacent BAFF or APRIL monomers are spatially close and can be linked to create single-chain homo- or hetero-ligands of defined stoichiometry. Similar to APRIL, heteromers consisting of one BAFF and two APRILs (BAA) bind to the receptors B cell maturation antigen (BCMA), transmembrane activator and CAML interactor (TACI) but not to the BAFF receptor (BAFFR). Heteromers consisting of one APRIL and two BAFF (ABB) bind to TACI and BCMA and weakly to BAFFR in accordance with the analysis of the receptor interaction sites in the crystallographic structure of ABB. Receptor binding correlated with activity in reporter cell line assays specific for BAFFR, TACI, or BCMA. Single-chain BAFF (BBB) and to a lesser extent single-chain ABB, but not APRIL or single-chain BAA, rescued BAFFR-dependent B cell maturation in BAFF-deficient mice. In conclusion, BAFF-APRIL heteromers of different stoichiometries have distinct receptor-binding properties and activities. Based on the observation that heteromers are less active than BAFF, we speculate that their physiological role might be to down-regulate BAFF activity.

Gyroscopic instability of a drop trapped inside an inclined circular hydraulic jump.

A drop of moderate size deposited inside a circular hydraulic jump remains trapped at the shock front and does not coalesce with the liquid flowing across the jump. For a small inclination of the plate on which the liquid is impacting, the drop does not always stay at the lowest position and oscillates around it with a sometimes large amplitude, and a frequency that slightly decreases with flow rate. We suggest that this striking behavior is linked to a gyroscopic instability in which the drop tries to keep constant its angular momentum while sliding along the jump.