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Abstract Introduction The Tobacco Heating System (THS) is a “heat-not-burn” tobacco product designed to generate significantly lower levels of harmful and potentially harmful constituents (HPHCs) and present lower risk of harm than cigarettes. This study assessed the exposure reduction to selected HPHCs in smokers switching to menthol Tobacco Heating System (mTHS) 2.2 compared with smokers continuing smoking menthol cigarettes (mCCs) and smoking abstinence (SA) for 5 days in a confined setting, followed by an 86-day ambulatory period. Methods A total of 160 healthy adult US smokers participated in this randomized, three-arm parallel group, controlled clinical study. Biomarkers of exposure to 16 HPHCs were measured in blood and 24-hour urine. Safety was monitored throughout the study. Information was also gathered on product evaluation, product use, subjective effects, and clinical risk markers (co-publication Part 2). Results Nicotine uptake was comparable in both exposure groups (mTHS:mCC ratio of 96% on day 90). On day 5, biomarker of exposure levels to other HPHCs were reduced by 51%–96% in the mTHS group compared with the mCC group, and these reductions were sustained for most biomarkers of exposure over ambulatory period. After 90 days of use, the level of satisfaction with mTHS and suppression of urge to smoke were comparable to mCC. Conclusion Switching from mCCs to mTHS significantly reduced the exposure to HPHCs to levels approaching those observed in subjects who abstained from smoking for the duration of the study. Implications This study compared the impact of switching to mTHS on biomarkers of exposure, relative to continued smoking or SA. Clinical Significance Switching to mTHS 2.2 led to significant reductions of exposure (total NNAL, total NNN, COHb, MHBMA, 3-HPMA, S-PMA, Total 1-OHP, 4-ABP, 1-NA, 2-NA, o-tol, CEMA, HEMA, HMPMA, and B[a]P) after 5 days in confinement, which were maintained throughout the subsequent ambulatory period of 86 days. The reductions were similar to those observed upon SA. Moderate compliance in the mTHS group during the ambulatory period was indicative of dual use of mTHS and mCC. mTHS provides an acceptable alternative to mCC for adult smokers. Trial Registration NCT01989156 (ClinicalTrials.gov).

Mastitis is a multifactorial infection of the udder potentially caused by many pathogens of varying severity and prevalence and it is one of the most common diseases on dairy farms. Limited information exists about the ecological interactions among pathogens in mastitis infections. This study aims (1) to identify the potential sources of the mastitis-causing pathogens at the farm level, (2) to analyse the statistical associations and dynamics of these pathogens over time in the milk microbiota, and (3) to assess their impact on somatic cell count (SCC) fluctuation. To address these objectives, two 4-month longitudinal studies were conducted on cows of six dairy farms in the Auvergne region of France. Milk and faeces were collected from a total of 33 cows, along with environmental samples (bedding and milk filter). A commercial qPCR kit (PathoProof ™ ) was used to quantify 15 mastitis-causing pathogens in these samples. The data were then processed using Principal Component Analysis, the Ward clustering method and discrete-time Markov chain models. Clustering analyses of quarter milk samples revealed distinct profiles of pathogen distribution associated with specific SCC and cow recovery dynamics. Notably, profiles involving Corynebacterium bovis , though considered a minor pathogen, were associated with persistent infections and variable SCC levels. We also described co-infections between C. bovis and Streptococcus uberis . Non- aureus staphylococci (NAS) were associated with a wide range of effects on udder health, as they constitute a diverse bacterial group, and detection of this group in the udder might generally not be sufficient to confirm a mastitis diagnosis. We highlight the importance of considering multi-pathogen associations and longitudinal dynamics in udder health management.

Abstract Introduction Modified-risk tobacco products are expected to reduce exposure to harmful and potentially harmful constituents of cigarette smoke, and ultimately reduce the health burden of smoking-related diseases. Clinically relevant risk markers of smoking-related diseases inform about the risk profile of new tobacco products in the absence of in-market epidemiological data. The menthol Tobacco Heating System 2.2 (mTHS) is a modified-risk tobacco product in development as an alternative to cigarettes (conventional cigarettes [CCs]). Methods In this parallel-group study, Japanese adult smokers (23–65 years; ≥10 mCCs/day) were randomized to mTHS, menthol CCs (mCC), or smoking abstinence (SA) for 5 days in confinement and 85 days in ambulatory settings. Endpoints included biomarkers of exposure to harmful and potentially harmful constituents and clinically relevant risk markers of smoking-related diseases. Results One-hundred and sixty participants were randomized to the mTHS (n = 78), mCC (n = 42), and SA (n = 40) groups. Switching to the mTHS was associated with reductions in biomarkers of exposure compared with continuing mCCs. Reductions in 8-epi-prostaglandin F2α (biomarker of oxidative stress), 11-dehydro-thromboxane B2 (biomarker of platelet activation), soluble intracellular adhesion molecule-1 (biomarker of endothelial function), and an increase in high-density lipoprotein cholesterol (biomarker of lipid metabolism) and forced expiratory volume in 1 second (biomarker of lung function) occurred in the mTHS group compared with the mCC group. The changes in the mTHS group approached those in the SA group. Conclusions Switching from mCCs to mTHS was associated with improvements in clinically relevant risk markers linked to mechanistic pathways involved in smoking-related diseases. Implications In this three-way randomized study, switching from menthol cigarettes to mTHS for 5 days in confinement and 85 days in ambulatory settings was associated with reductions in biomarkers of exposure to cigarette smoke, and changes were observed in clinically relevant biomarkers of oxidative stress (8-epi-prostaglandin F2α), platelet activity (11-dehydro-thromboxane B2), endothelial function (soluble intracellular adhesion molecule-1), lipid metabolism (high-density lipoprotein cholesterol) and lung function (forced expiratory volume in 1 second), similar to the SA group. The results suggest that switching to the mTHS has the potential to reduce the adverse health effects of conventional cigarettes.

Abstract Introduction The menthol Tobacco Heating System 2.2 (mTHS) is a newly developed candidate modified-risk tobacco product intended to reduce exposure to the harmful and potentially harmful constituents (HPHCs) of conventional cigarette (CC) smoke. This study examined the impact of switching to mTHS on biomarkers of exposure to HPHCs relative to menthol CCs (mCCs) and smoking abstinence (SA). Methods In this three-arm, parallel-group study, 160 Japanese adult smokers (23–65 years; smoking ≥10 mCCs per day) were randomized to mTHS (n = 78), mCC (n = 42), or SA (n = 40) for 5 days in confinement and 85 days in ambulatory settings. Endpoints included biomarkers of exposure to HPHCs, human puffing topography, safety, and subjective effects of smoking measures. Results After 5 days of product use, the concentrations of carboxyhemoglobin, 3-hydroxypropylmercapturic acid, monohydroxybutenyl mercapturic acid, and S-phenylmercapturic acid were 55%, 49%, 87%, and 89% lower (p < .001), respectively, in the mTHS group than in the mCC group. Other biomarkers of exposure (measured as secondary endpoints) were 50%–94% lower in the mTHS group than in the mCC group on day 5. These reductions in the mTHS group were maintained at day 90, similar to the SA group. Switching to mTHS was associated with changes in human puffing topography (shorter puff intervals and more frequent puffs). The urge-to-smoke and smoking satisfaction levels on day 90 were similar in the mTHS and the mCC groups. Conclusion Switching from mCCs to mTHS significantly reduced exposure to HPHCs relative to continuing smoking mCCs with concentrations similar to those observed following SA in Japanese adult smokers. Implications This randomized study compared the impact of switching to a modified-risk tobacco product candidate mTHS on biomarkers of exposure to HPHCs of cigarette smoke relative to continuing smoking cigarettes or abstaining from smoking in sequential confinement and ambulatory settings. The study showed that switching to mTHS was associated with significant biomarker reductions within 5 days in confinement, these reductions being maintained throughout the ambulatory setting up to day 90. The results provide evidence that switching to mTHS reduces real-life exposure to HPHCs in adult smokers.

Abstract Introduction Tobacco Heating System (THS) 2.2, a candidate modified-risk tobacco product, aims at offering an alternative to cigarettes for smokers while substantially reducing the exposure to harmful and potentially harmful constituents found in cigarette smoke. Methods One hundred and sixty healthy adult US smokers participated in this randomized, three-arm parallel group, controlled clinical study. Subjects were randomized in a 2:1:1 ratio to menthol Tobacco Heating System 2.2 (mTHS), menthol cigarette, or smoking abstinence for 5 days in confinement and 86 subsequent ambulatory days. Endpoints included biomarkers of exposure to harmful and potentially harmful constituents (reported in our co-publication, Part 1) and biomarkers of potential harm (BOPH). Results Compliance (protocol and allocated product exposure) was 51% and 18% in the mTHS and smoking abstinence arms, respectively, on day 90. Nonetheless, favorable changes in BOPHs of lipid metabolism (total cholesterol and high- and low-density cholesterol), endothelial dysfunction (soluble intercellular adhesion molecule-1), oxidative stress (8-epi-prostaglandin F2α), and cardiovascular risk factors (eg, high-sensitivity C-reactive protein) were observed in the mTHS group. Favorable effects in other BOPHs, including ones related to platelet activation (11-dehydrothromboxane B2) and metabolic syndrome (glucose), were more pronounced in normal weight subjects. Conclusions The results suggest that the reduced exposure demonstrated when switching to mTHS is associated with overall improvements in BOPHs, which are indicative of pathomechanistic pathways underlying the development of smoking-related diseases, with some stronger effects in normal weight subjects. Implications Switching to mTHS was associated with favorable changes for some BOPHs indicative of biological pathway alterations (eg, oxidative stress and endothelial dysfunction). The results suggest that switching to mTHS has the potential to reduce the adverse health effects of smoking and ultimately the risk of smoking-related diseases. Switching to mTHS for 90 days led to reductions in a number of biomarkers of exposure in smokers, relative to those who continued smoking cigarettes, which were close to those observed when stopping smoking (reported in our co-publication, Part 1). Initial findings suggest reduced levels of 8-epi-prostaglandin F2α and intercellular adhesion molecule 1, when switching to mTHS for 90 days. These changes are comparable to what is observed upon smoking cessation. In normal weight subjects, additional favorable changes were seen in 11-dehydrothromboxane B2, fibrinogen, homocysteine, hs-CRP, percentage of predicted forced expiratory volume in 1 second, systolic blood pressure, diastolic blood pressure, glucose, high-density lipoprotein, apolipoprotein A1, and triglycerides. Trial registration NCT01989156.

Ixodes ricinus ticks (Acari: Ixodidae) are the most important vector for Lyme borreliosis in Europe. As climate change might affect their distributions and activities, this study aimed to determine the effects of environmental factors, i.e., meteorological, bioclimatic, and habitat characteristics on host-seeking (questing) activity of I. ricinus nymphs, an important stage in disease transmissions, across diverse climatic types in France over 8 years. Questing activity was observed using a repeated removal sampling with a cloth-dragging technique in 11 sampling sites from 7 tick observatories from 2014 to 2021 at approximately 1-month intervals, involving 631 sampling campaigns. Three phenological patterns were observed, potentially following a climatic gradient. The mixed-effects negative binomial regression revealed that observed nymph counts were driven by different interval-average meteorological variables, including 1-month moving average temperature, previous 3-to-6-month moving average temperature, and 6-month moving average minimum relative humidity. The interaction effects indicated that the phenology in colder climates peaked differently from that of warmer climates. Also, land cover characteristics that support the highest baseline abundance were moderate forest fragmentation with transition borders with agricultural areas. Finally, our model could potentially be used to predict seasonal human-tick exposure risks in France that could contribute to mitigating Lyme borreliosis risk.

In Europe, Ixodes ticks are major vectors for both human and livestock pathogens, with the most widespread species, Ixodes ricinus , being responsible for the transmission of the pathogenic agent of Lyme disease, Borrelia burgdorferi sensu lato. The disease is endemic in France, where the number of new human cases per year was estimated at 39,052 in 2023. I. ricinus is widely distributed in France, particularly in Auvergne-Rhône-Alpes, where its abundance is not always well known. Often, estimation of questing tick abundance is based on a single observation from several sites; moreover, depending on sampling conditions, the efficiency of sampling with cloth dragging is variable, but is generally low. Even when standardised protocols are used, abundance indicators and sampling rates are influenced by various factors including population dynamics, ground vegetation, soil layers and meteorology. One approach that can be employed to account for the impact of these factors on variations in sampling rate is the use of removal samplings, i.e. several successive samplings. The TELETIQ project (https://teletiq.clermont.hub.inrae.fr/) was interested in mobile phone and participatory science data for the estimation and understanding of the risk of transmission of environmental diseases with an application to diseases transmitted by ticks. It aimed to explore how data from information and communication technologies can be used to improve the estimation and understanding of the risk of transmission of diseases related to the environment. As part of this project, questing ticks were sampled in the field in 15 sites located in the Auvergne-Rhône-Alpes Region (France). We designed an innovative protocol that combined three months of sampling (to include the time of peak tick activity), two transects for each site (to increase statistical power) and the removal sampling method (to take account of the variation in the sampling rate due to ground vegetation). A sampling protocol was designed to collect ticks using the cloth-dragging method. In each site, sampling was conducted along two transects, with ten sub-transects (ST) per transect. Each sub-transect was subjected to three successive rounds of sampling per month, from April to June, 2018. Based on this, we created a dataset of questing tick abundance and information on local environmental conditions. Over the three months of sampling, 2,274 questing ticks were captured across the 15 sites. This total included 2,205 questing nymphs, 30 questing adult females and 39 questing adult males. I. ricinus represented 100% of the identified ticks. Of the 2,205 nymphs sampled over the three months from April to June 2018, 62% were sampled (n = 1,367) in the first round of sampling, 24.5% (n = 540) in the second and 13.5% (n = 298) in the third. In 29.7% of STs (n = 267/900), no nymphs were collected in any of the three successive rounds of sampling confirming a strong presumption of absence. In 57.9% of STs (n = 521/900), at least one nymph was collected in the first round of sampling. In 112 of the remaining STs — in which no nymphs were detected in the first round of sampling — successive sampling did reveal the presence of nymphs (12.4% of the 900 total STs, 168 nymphs collected overall, representing 7.62% of the total number of nymphs collected in this project). Without a removal sampling design, that is, with only a single sampling occasion, these STs would have been considered tick-free. The information in this dataset on the local abundance of questing I. ricinus ticks can be used to determine the best way to collect data in the field, based on the sampling rate and vegetation type.

Background: In Europe, ticks are responsible for the transmission of several pathogens of medical importance, including bacteria of the Borrelia burgdorferi (s.l.) complex, the agents of Lyme borreliosis. In France, the Auvergne Rhône-Alpes region is considered a hot spot for human tick-borne pathogen infections, with an estimated annual rate of 156 cases of Lyme borreliosis per 100,000 inhabitants. Although several studies have assessed the abundance of ticks in rural areas, little consideration has been given thus far to urban green spaces in France. Methods: This study aimed to estimate tick abundance in three parks, two urban (U1, U2) and one peri-urban (PU), in and around the city of Lyon (France). A forest in a rural area was used as a control (C). Tick sampling campaigns were performed in each site in April, May, June, July, and October 2019 using the dragging method. One hundred transects of 10 m 2 each were randomly chosen in each park in places frequented by humans. The sampling sessions were carried out under semi-controlled abiotic conditions. Ticks were stored in 70% ethanol and identified to species and developmental stage under a light microscope using morphological keys. Results: A total of seven ticks (nymphs and adults) were collected in the two urban parks (six in U1 and one in U2), while 499 ticks were sampled in the peri-urban park. Of the 506 ticks collected, 504 were identified as Ixodes ricinus, one as Dermacentor marginatus, and one as Ixodes frontalis. In the peri-urban park, ticks were mainly collected under the forest cover and at forest edges. Tick density under forest cover was 7.1 times higher in the control site than in the peri-urban park throughout the survey period. Conclusions: This study confirmed the presence of ticks in all of the parks surveyed, although their occurrence in the urban parks was very rare compared to the peri-urban park and the control site. These results should serve as a basis for the implementation of preventive measures.

Many pathogens are maintained by multiple host species and involve multiple strains with potentially different phenotypic characteristics. Disentangling transmission patterns in such systems is often challenging, yet investigating how different host species contribute to transmission is crucial to properly assess and manage disease risk. We aim to reveal transmission cycles of bacteria within the Borrelia burgdorferi species complex, which include Lyme disease agents. We characterized Borrelia genotypes found in 488 infected Ixodes ricinus nymphs collected in the S é nart Forest located near Paris (France). These genotypes were compared to those observed in three sympatric species of small mammals and network analyses reveal four independent transmission cycles. Statistical modelling shows that two cycles involving chipmunks, an introduced species, and non-sampled host species such as birds, are responsible for the majority of tick infections. In contrast, the cycle involving native bank voles only accounts for a small proportion of infected ticks. Genotypes associated with the two primary transmission cycles were isolated from Lyme disease patients, confirming the epidemiological threat posed by these strains. Our work demonstrates that combining high-throughput sequence typing with networks tools and statistical modeling is a promising approach for characterizing transmission cycles of multi-host pathogens in complex ecological settings.

Abstract Mastitis is a multifactorial infection of the udder potentially caused by many pathogens of varying severity and prevalence. They are one of the most common diseases on dairy farms. Limited information exists about the interactions between pathogens in mastitis infections. The first aim of this study was to investigate the dynamics of pathogens and their associations in the udder microbiota. We then explored the impact of these dynamics on mastitis risk, in order to gain a better understanding of this disease. We finally looked for factors influencing these dynamics and the potential sources of the studied pathogens at farm level. To address these objectives, two four-month longitudinal studies were conducted on cows of six dairy farms in the Auvergne region of France. Milk and faeces were collected from 33 cows, along with environmental samples (bedding and milk filter). The 16S DNA in these samples was analysed, using a commercial qPCR kit (PathoProof™) to detect 15 mastitis-causing pathogens. The data were then processed using principal component analysis, the Ward clustering method and discrete-time Markov chain models. We classified pathogens according to their distribution in the different compartments. Clustering analyses of milk quarter samples revealed distinct profiles of pathogen distribution associated with different somatic cell counts and cow recovery dynamics. According to these dynamics, C. bovis , though considered a minor pathogen, and S. uberis were pivotal in the definition of milk pathogen profiles, with the possible involvement of non- aureus staphylococci.