Impact of switching from cigarette smoking to tobacco heating system use on biomarkers of potential harm in a randomized trial.

BACKGROUND: Smoking cessation reduces the risk of developing smoking-related diseases. Although smoking prevalence has declined, many continue smoking cigarettes. Switching completely to smoke-free alternatives like the Tobacco Heating System (THS) 2.2-a heated tobacco product for which there is evidence demonstrating significantly reduced formation and exposure to harmful chemicals compared to cigarettes-has the potential to reduce the harm caused by continuing to smoke cigarettes. METHODS: We conducted a 6-month clinical study (NCT02396381) with a 6-month extension (NCT02649556), initially randomizing 984 adult smokers to continue smoking or switch to THS (non-mentholated), of which 672 continued into the extension study. Endpoints were evaluated at baseline and at 3, 6, and 12 months. We longitudinally assessed biomarkers of potential harm (BoPHs) known to be reversible upon smoking cessation as indicators of pathways involved in the pathogenesis of cardiovascular or respiratory diseases and carcinogenicity. The need to cough and safety profile were also assessed. Impact on eight key BoPHs was used as a proxy to evaluate harm reduction potential. RESULTS: At 12 months, comparison of BoPH levels between the predominant THS use and cigarette smoking groups showed a positive effect in favor of switching, partially or in full, to THS. CONCLUSION: These results provide additional evidence of the harm reduction potential of THS for smokers who would otherwise continue smoking, but they need to be verified in long-term confirmatory studies. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT0264955. Date of registration: January 7, 2016 https://clinicaltrials.gov/ct2/show/NCT02649556.

Towards a Non-Biased Formaldehyde Quantification in Leather: New Derivatization Conditions before HPLC Analysis of 2,4-Dinitrophenylhydrazine Derivatives.

In leathers, formaldehyde is currently analyzed according to EN ISO 17226-1 standard, by reversed phase liquid chromatography after off-line precolumn derivatization with 2,4 dinitrophenylhydrazine (DNPH) in strong acidic conditions. We first demonstrate that this standard is not adapted to leather retanned with resins likely to release formaldehyde by hydrolysis. Indeed, formaldehyde content may be largely overestimated due to concomitant resin hydrolysis (in harsh acidic conditions) that releases formaldehyde during the derivatization step and during the waiting time on autosampler before analysis. Therefore, we thoroughly studied the derivatization step in order to propose new derivatization conditions. Replacing orthophosphoric acid by less acidic buffer solutions is not enough to avoid hydrolysis. A derivatization without adding acid is realized by solubilizing DNPH in acetonitrile instead of orthophosphoric acid. These conditions lead to a complete derivatization of formaldehyde in 3 h at 50 °C (in a water bath) while avoiding the hydrolysis of co-extracted dicyandiamide and melamine resins. The as-obtained leather extracts are stable over time. Formaldehyde contents found with this method agree with the formaldehyde content measured immediately at the end of derivatization reaction in standard conditions or with formaldehyde content measured by a home-designed flow injection analysis with acetylacetone online derivatization and UV detection.

Robotic gait training and botulinum toxin injection improve gait in the chronic post-stroke phase: A randomized controlled trial.

BACKGROUND: Improving walking ability is one of the main goals of rehabilitation after stroke. When lower limb spasticity increases walking difficulty, botulinum toxin type A (BTx-A) injections can be combined with non-pharmacologic interventions such as intensive rehabilitation using a robotic approach. To the best of our knowledge, no comparisons have been made between the efficacy of robotic gait training and conventional physical therapy in combination with BTx-A injections. OBJECTIVE: To conduct a randomized controlled trial to compare the efficacy on gait of robotic gait training versus conventional physiotherapy after BTx-A injection into the spastic triceps surae in people after stroke. METHOD: Thirty-three participants in the chronic stroke phase with triceps surae spasticity inducing gait impairment were included. After BTx-A injection, participants were randomized into 2 groups. Group A underwent robotic gait training (Lokomat®) for 2 weeks, followed by conventional physiotherapy for 2 weeks (n = 15) and Group B underwent the same treatment in reverse order (n = 18). The efficacy of these methods was tested using the 6-minute walk test (6MWT), comparing post-test 1 and post-test 2 with the pre-test. RESULTS: After the first period, the 6MWT increased significantly more in Group A than in Group B: the mean difference between the interventions was 33 m (95%CI 9; 58 p = 0.007; g = 0.95), in favor of Group A; after the second period, the 6MWT increased in both groups, but the 30 m difference between the groups still remained (95%CI 5; 55 p = 0.019; g = 0.73). CONCLUSION: Two weeks of robotic gait training performed 2 weeks after BTx-A injections improved walking performance more than conventional physiotherapy. Large-scale studies are now required on the timing of robotic rehabilitation after BTx-A injection.

Fitness and walking outcomes following aerobic and lower extremity strength training in facioscapulohumeral dystrophy: a case series.

Facioscapulohumeral muscular dystrophy (FSHD) is a common form of adult muscular dystrophy often resulting also in cardiorespiratory deconditioning and weakness of the lower limbs. Although previous studies examined outcomes of interventions aimed at improving either cardiorespiratory fitness or muscle strength, the potential benefits of a rehabilitation program targeting both remain unexplored. Thus, the aim of this study was to evaluate changes following participation in a rehabilitation program combining aerobic and strength exercises. We conducted a retrospective analysis of 10 subjects with FSHD who participated in our rehabilitation program during 2018 and 2019. Each of the 20 sessions consisted of aerobic training on a cycloergometer and a moderate lower limb strength exercises on an isokinetic machine in combination with conventional therapy. The primary outcomes were walking speed, aerobic performance and isokinetic strength of the knee extensors and flexors. The secondary outcomes were fatigue, insomnia. VO2max and walking speed increased significantly by 2.125 ml·kg-1·min-1 [95% confidence interval (CI): 0.75-3.62, P = 0.022] and 0.28 m/s (95% CI: 0.16-0.4, P = 0.002), respectively. The effect size was small for V02max (Hedge's g, 0.44; 95% CI: -0.5 to 1.37) and large for walking speed (Hedge's g, 0.99; 95% CI: 0.06-1.92). The knee flexor strength significantly increased at rehabilitation discharge (repeated measures analysis of variance P = 0.004). Positive changes in fatigue and insomnia were also observed. Our preliminary results provide evidence that a relatively short course of a comprehensive rehabilitation program targeting both cardiorespiratory fitness and knee muscle strength can be beneficial for people with FSHD, which warrants further prospective studies.

Effect of Switching to the Tobacco Heating System Versus Continued Cigarette Smoking on Chronic Generalized Periodontitis Treatment Outcome: Protocol for a Randomized Controlled Multicenter Study.

BACKGROUND: Smoking is a significant risk factor for periodontal disease and tooth loss, as shown in several clinical studies comparing smokers and nonsmokers. Although only a few longitudinal studies have assessed the outcome of periodontal disease after smoking cessation, they indicated that recovery after nonsurgical treatment was more successful in those who had quit smoking. As part of tobacco harm reduction strategies, substituting cigarettes with alternative, less harmful tobacco products is an approach complementary to cessation for smokers who would otherwise continue to smoke. The Tobacco Heating System (THS), developed by Philip Morris International (commercialized as IQOS), is part of the heat-not-burn product category. The IQOS device electrically heats tobacco instead of burning it, at much lower temperatures than cigarettes, thereby producing substantially lower levels of harmful and potentially harmful constituents, while providing the nicotine, taste, ritual, and a sensory experience that closely parallel those of cigarettes. Phillip Morris International has published the results from a broad clinical assessment program, which was established to scientifically substantiate the harm reduction potential of the THS among adult healthy smokers switching to the THS. The program is now progressing toward including adult smokers with smoking-related diseases. OBJECTIVE: The goal of this study is to demonstrate favorable changes of periodontal endpoints in response to mechanical periodontal therapy in patients with generalized chronic periodontitis who completely switched to THS use compared with continued cigarette smoking. METHODS: This is a randomized controlled two-arm parallel-group multicenter Japanese study conducted in patients with chronic generalized periodontitis who switch from cigarettes to THS compared with smokers continuing to smoke cigarettes for 6 months. The patients were treated with mechanical periodontal therapy as per standard of care in Japan. The primary objective of the study is to demonstrate the beneficial effect of switching to THS use compared with continued cigarette smoking on pocket depth (PD) reduction in all sites with an initial PD≥4 mm. The secondary objectives include evaluation of other periodontal parameters (eg, clinical attachment level or gingival inflammation) and overall oral health status upon switching to THS. Safety was monitored throughout the study. RESULTS: In total, 172 subjects were randomized to the cigarette (n=86) or THS (n=86) groups, and all 172 completed the study. The conduct phase of the study is completed, while data cleaning and analyses are ongoing. CONCLUSIONS: This study is the first to test a heat-not-burn tobacco product in smokers with an already established disease. The results should further strengthen the evidence that switching to THS can significantly reduce the risk of smoking-related diseases if favorable changes in the evolution of chronic generalized periodontitis after mechanical therapy are found when compared with continued cigarette smoking. TRIAL REGISTRATION: ClinicalTrials.gov NCT03364751; https://clinicaltrials.gov/ct2/show/NCT03364751. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/15350.

Reduced levels of biomarkers of exposure in smokers switching to the Carbon-Heated Tobacco Product 1.0: a controlled, randomized, open-label 5-day exposure trial.

In addition to smoking cessation, for those who would otherwise continue to smoke, replacing cigarettes with less harmful alternatives can reduce the harms of smoking. Heating instead of burning tobacco reduces, or eliminates, the formation of harmful and potentially harmful constituents (HPHC) that are found in cigarette smoke. The Carbon-Heated Tobacco Product (CHTP), a heat-not-burn tobacco product, mimics the cigarette smoking ritual. This randomized, open-label, two-arm, parallel-group, short-term confinement study tested the hypothesis that the geometric means of the BoExp levels for subjects switching to CHTP 1.0 for 5 days are lower relative to those continuing to smoke cigarettes. Biomarkers of exposure (BoExp), including nicotine, urinary excretion of mutagenic constituents (Ames test), and cytochrome P450 (CYP) 1A2 activity, were measured in blood and/or 24-h urine samples during ad libitum product use. Nicotine exposure remained at similar levels in individuals using CHTP as in those continuing to smoke cigarettes. Switching to CHTP resulted in marked decreases in all other urinary BoExp (56-97%), carboxyhemoglobin (59%), urinary mutagenic constituents, and CYP1A2 activity compared with continued cigarette smoking. Our results provide evidence of decreased exposure to 15 selected HPHCs in smokers switching from cigarettes to exclusive CHTP use.Trial registration ClinicalTrials.gov: NCT02503254; Date of first registration: 20/07/2015 https://www.clinicaltrials.gov/ct2/show/NCT02503254 .Study protocol Study protocol published at: https://www.clinicaltrials.gov/ProvidedDocs/54/NCT02503254/Prot_000.pdf .

Impact of switching to a heat-not-burn tobacco product on CYP1A2 activity.

BACKGROUND: Cigarette smoking induces cytochrome P450 1A2 (CYP1A2) expression and activity, while smoking cessation normalizes the levels of this enzyme. The aim of this publication is to summarize the data on CYP1A2 gene expression and activity in preclinical and clinical studies on the Tobacco Heating System (THS), currently marketed as IQOS® with HEETs®, and to summarize the potential effects on CYP1A2 to be expected upon switching to reduced-risk products (RRPs). METHODS: We summarized PMI's preclinical and clinical data on the effects of switching from cigarette smoking to THS. RESULTS: Data from four preclinical mouse and rat studies showed that, upon either cessation of cigarette smoke exposure or switching to THS exposure, the upregulation of CYP1A2 observed with exposure to cigarette smoke reverted close to fresh-air levels. Data from four clinical studies yielded similar results on CYP1A2 activity within a time frame of five days. Furthermore, the effects of switching to THS were similar to those seen after smoking cessation. CONCLUSIONS: Because smoking cessation and switching to either electronic cigarettes or THS seem to have similar effects on CYP1A2 activity, the same measures taken for patients treated with narrow therapeutic index drugs that are metabolized by CYP1A2 and who quit smoking should be recommended for those switching to RRPs.

Hexavalent chromium release from leather over time natural ageing vs accelerated ageing according to a multivariate approach.

European restriction limits the hexavalent chromium content to not more than 3 mg/kg in leather products. Owing to the evolution of hexavalent chromium content in leathers over time, it's difficult to guarantee the products will be harmless for consumers. The designing of an accelerated and representative artificial ageing procedure is therefore highly desirable. This article proposes a thorough study of the influence of storage conditions on the formation of hexavalent chromium in 4 bovine leathers. A factorial design of experiment was built with the following factors: temperature of 40-80 °C, relative humidity of 20-50%, presence or not of UV and exposure duration of 24-48 h. The results of these artificial ageings demonstrate that a high temperature, a dry atmosphere and the presence of light favor the formation of hexavalent chromium and that synergistic effects operate between temperature/humidity, temperature/UV and humidity/UV. At the same time, the leathers were subjected to a natural ageing for 12 months with a weekly hexavalent chromium analysis. The principal component analysis of the artificial ageing tests combined with the natural ageing tests, show that the artificial ageings 40 °C-50%RH-UV-48 h and 40 °C-20%RH-UV-24 h best simulate a natural ageing in the tannery, whatever the leather studied.

Effects of Switching to a Heat-Not-Burn Tobacco Product on Biologically Relevant Biomarkers to Assess a Candidate Modified Risk Tobacco Product: A Randomized Trial.

BACKGROUND: Cigarette smoking increases the risk of chronic diseases; heating instead of burning tobacco can lower these risks, contributing to tobacco harm reduction. This study (with 984 adult American smokers) examined whether favorable changes occur in 8 co-primary endpoints (HDL-C, WBC, FEV1%pred, COHb, Total NNAL, sICAM-1, 11-DTX-B2, 8-epi-PGF2α) indicative of biological and functional effects when cigarette smokers switch to the heat-not-burn Tobacco Heating System 2.2 (THS). Additionally, these biomarkers of exposure (BoExp) were quantified: MHBMA, 3-HPMA, Total NNN, CEMA, 3-OH-B[a]P, HMPMA, Total 1-OHP, NEQ, and CO exhaled. METHODS: Participants were randomized to continued smoking of their preferred cigarette brand (n = 496) or to using THS (IQOS brand; n = 488) for 6 months. THS has a maximum heating temperature of 350°C, delivering 1.21 mg nicotine/stick and 3.94 mg glycerin/stick under the Health Canada Intense smoking regimen. RESULTS: The main outcome was a favorable change 6 months after baseline, with statistically significant improvements in 5 of 8 biomarkers of effect (HDL-C, WBC, FEV1%pred, COHb, Total NNAL) when smokers switched to THS compared with those who continued to smoke cigarettes. Likewise, BoExp were markedly reduced. CONCLUSIONS: All endpoints showed favorable changes in the same direction as with smoking cessation and improved biological effects were observed in smokers who predominantly used THS compared with continued cigarette smoking, with similar nicotine levels in both groups. IMPACT: Improvements in 5 of 8 biomarkers of effect are supportive of the research hypothesis, suggestive of disease risk reduction potential for smokers switching to THS instead of continuing to smoke cigarettes.

Comminution of Dry Lignocellulosic Biomass: Part II. Technologies, Improvement of Milling Performances, and Security Issues.

Lignocellulosic feedstocks present a growing interest in many industrial processes as they are an ecological alternative to petroleum-based products. Generally, the size of plant raw materials needs to be reduced by milling step(s), to increase density, facilitate transport and storage, and to increase reactivity. However, this unit operation can prove to be important in term of investments, functioning costs, and energy consumption if the process is not fully adapted to the histological structure of the plant material, possibly challenging the profitability of the whole chain of the biomass conversion. In this paper, the different technologies that can be used for the milling of lignocellulosic biomass were reviewed and different avenues are suggested to improve the milling performances thanks to thermal pretreatments. Based on examples on wheat straw milling, the main points to take into consideration in the choice of a milling technologies have been highlighted in regards to the specifications of ground powder. A specific focus on the hazards associated to the milling and the manipulation of fine biomass particles is also realized at the end of the paper from the perspective of industrial applications.

Comminution of Dry Lignocellulosic Biomass, a Review: Part I. From Fundamental Mechanisms to Milling Behaviour.

The comminution of lignocellulosic biomass is a key operation for many applications as bio-based materials, bio-energy or green chemistry. The grinder used can have a significant impact on the properties of the ground powders, of those of the end-products and on the energy consumption. Since several years, the milling of lignocellulosic biomass has been the subject of numerous studies most often focused on specific materials and/or applications but there is still a lack of generic knowledge about the relation between the histological structure of the raw materials, the milling technologies and the physical and chemical properties of the powders. This review aims to point out the main process parameters and plant raw material properties that influence the milling operation and their consequences on the properties of ground powders and on the energy consumption during the comminution.

Evaluation of Biological and Functional Changes in Healthy Smokers Switching to the Tobacco Heating System 2.2 Versus Continued Tobacco Smoking: Protocol for a Randomized, Controlled, Multicenter Study.

BACKGROUND: Tobacco harm reduction, substituting less harmful tobacco products for combustible cigarettes, is a complementary approach for smokers who would otherwise continue to smoke. The Philip Morris International (PMI) Tobacco Heating System (THS) 2.2 is a novel tobacco product with the potential to reduce the risk of harm in smokers compared to continued smoking of combustible cigarettes. It heats tobacco electrically in a controlled manner, never allowing the temperature to exceed 350°C, thereby preventing the combustion process from taking place and producing substantially lower levels of toxicants while providing nicotine, taste, ritual, and a sensory experience that closely parallels combustible cigarettes. Previous clinical studies have demonstrated reduced exposure to the toxicants (approaching the levels observed after quitting) for smokers who switched to THS 2.2, for three months. For adult smokers who would otherwise continue smoking combustible cigarettes, switching to THS 2.2 may represent an alternative way to reduce the risk of tobacco-related diseases. OBJECTIVE: This study aimed to further substantiate the harm reduction potential of THS 2.2 by demonstrating favorable changes in a set of 8 coprimary endpoints, representative of pathomechanistic pathways (ie, inflammation, oxidative stress, lipid metabolism, respiratory function, and genotoxicity), linked to smoking-related diseases, in smokers switching from combustible cigarettes to THS 2.2. METHODS: This study was a randomized, controlled, two-arm parallel group, multicenter ambulatory US study conducted in healthy adult smokers switching from combustible cigarettes to THS 2.2 compared with smokers continuing to smoke combustible cigarettes for six months. Subjects had a smoking history of at least ten years and did not intend to quit within the next six months. RESULTS: Enrollment started in March 2015 and the trial was completed in September 2016. In total, 984 subjects were randomized (combustible cigarettes, n=483; THS 2.2, n=477), and 803 completed the study. The results are expected to be available in a subsequent publication in 2019. CONCLUSIONS: In this paper, we describe the rationale and design for this clinical study that focused on the evaluation of THS 2.2's potential to reduce the risk of smoking-related diseases compared with that of combustible cigarettes. This study will provide insights regarding favorable changes in biological and functional endpoints informed by effects known to be seen upon smoking cessation. TRIAL REGISTRATION: ClinicalTrials.gov NCT02396381; http://clinicaltrials.gov/ct2/show/NCT02396381 (Archived by WebCite at http://www.webcitation.org/71PCRdagP). REGISTERED REPORT IDENTIFIER: RR1-10.2196/11294.

Fluorescence spectroscopy to study dissolved organic matter interactions with agrochemicals applied in Swiss vineyards.

UV/Vis fluorescence spectroscopy was used to study the possible interactions of dissolved organic matter (DOM) with the herbicide glyphosate and copper-based fungicide used in vineyards. The study focused on the role of DOM in the transport of these micropollutants from parcels to surface waters (river, lake). Soil solution and river water samples were collected in the Lavaux vineyard area, western Switzerland. Their fluorescence excitation emission matrices (EEM) were decomposed using parallel factor (PARAFAC) analysis, and compared to their content in glyphosate and copper. PARAFAC analysis of EEM of both types of samples showed the contribution of protein-like and humic-like fluorophores. In soil water samples, complexes between fulvic-like and humic-like fluorophores of DOM, copper, and glyphosate were likely formed. In surface water, DOM-copper and glyphosate-copper interactions were observed, but not between glyphosate and DOM.