Molecular hydrogen (H2 gas) has emerged as a promising therapeutic agent with reported benefits across oxidative stress, inflammation, cardiovascular, and neurodegenerative conditions. Among administration routes, inhalation provides direct systemic delivery but has been hindered by a lack of individualization, methodological inconsistencies, misinterpretation of concentration, and safety concerns. We propose that fraction of inspired hydrogen (FiH2), defined at the airway opening rather than by source gas concentration (FH2) or flow rate, should be considered the standardized metric for dosing, akin to oxygen therapy. This directly links inspired H2 at the airway opening to resulting blood concentrations via Dalton’s and Henry’s laws, thereby enabling consistent dosing, interpretation of clinical data, and comparability across studies. A targeted analysis of experimental and clinical literature was used to identify H2 concentration ranges associated with minimum and optimal biological effects. Deterministic respiratory-physiology in silico modeling was then used to estimate the FiH2 during nasal cannula H2 administration under practical breathing conditions, accounting for minute ventilation, inspiratory flow dynamics, and duty cycle, and to derive H2 flow-rate requirements. Evidence indicates that therapeutic effects typically require blood concentrations of 2–10 µM, corresponding to 1

Introduction Molecular hydrogen (H2) has significant therapeutic potential, in particular in cardiac diseases. These are attributed to its anti-oxidant, anti-apoptotic and anti-inflammatory properties. Current studies strongly suggest that H2 could protect cardiac function against ischemia and reperfusion syndromes. Objective This study investigates whether H2 enrichment of perfusion solutions exerts cardioprotective effects during ischemia and/or reperfusion on an isolated heart perfusion model. Method A total of 47 male Wistar rats were used in two different procedures. In the first one, 21 rats were randomly divided into two groups: control (n=11) and H2 (n=10). After anesthesia, hearts were excised and placed in ice-cold Krebs-Henseleit Buffer (KHB), then mounted on a Langendorff perfusion system (100cmH2O). A water-filled balloon was inserted into the left ventricle and inflated to impose an end-diastolic pressure of 5–8mmHg. After 20min of pre-ischemic aerobic perfusion with KHB saturated with 85.5% O2/4.5% CO2/10% N2 (control) or 10% H2, hearts were subjected to 30minutes global, total, normothermic ischemia followed by 50minutes of reperfusion. In the second procedure, 26 rats were randomly distributed into two groups: control (n=13) and H2 (n=13). Hearts were perfused according to the same protocol but were frozen at the end of the 30min of ischemia for molecular analysis. Statistical analysis was performed by Unpaired t-test using GraphPad. Results The first procedure evidenced an absence of difference between groups in terms of post-ischemic functional recovery. In contrast, statistical analysis of ischemic contracture in pooled procedures revealed an increase in the time-to-onset of contracture (TTOC) in the H2 groups compared to controls (TTOC=10.4±0.5minutes in controls [n=23] vs. 12.3±0.6minutes in H2 [n=22]; P<0.01). Conclusion Perfusion with H2-enriched KHB does not protect isolated rat hearts from post-ischemic contractile dysfunction. However, it significantly delays the onset of ischemic contracture, suggesting a preservation of calcium homeostasis during ischemia. The hypothesis of H2-mediated protection against sarcoplasmic reticulum stress is currently being analyzed. This work could have significant implications for the protection of the ischemic myocardium, particularly in improving cardioplegia protocols designed to limit primary graft dysfunction after cardiac transplantation.

Inulin consumption and dihydrogen (H2) administration both exert antitumor effects on preclinical models as well as in clinical trials. As H2 is one of the major byproducts of inulin fermentation by bacterial species of the gut microbiota (GM), we hypothesized that H2 could mediate the antitumor effects of inulin. To provide evidence in favor of this hypothesis, we first determined the pattern of H2-exposure to which mice are subjected after inulin administration and developed an inhaled hydrogen therapy (H2T) protocol replicating this pattern. We then compared the effects on circulating immunity of a two-week daily inulin gavage with those of the corresponding H2T. We also compared the effects of inulin supplementation to those of the corresponding H2T on implanted melanoma growth and infiltration by T lymphocytes. Inulin and H2T induced a similar increase in circulating CD4+ and CD8+ T cells. In addition, both treatments similarly inhibited melanoma tumor growth. These results support a mechanism by which the H2 resulting from inulin fermentation by the GM diffuses across the intestinal barrier and stimulates the immunosurveillance responsible for the antitumor effect.

The invasive nature of sample collection for studying the small intestinal (SI) microbiome often results in its poor characterization. This study evaluated a novel ingestible medical device (MD) for SI luminal sample collection. A monocentric interventional trial (NCT05477069) was conducted on 15 healthy subjects. Metagenomics, metabolomics and culturomics assessed the MD's effectiveness in characterizing the healthy SI microbiome and identifying potential biomarkers. The SI microbiota differed significantly from the fecal microbiota, displaying high inter-individual variability, lower species richness, and reduced alpha diversity. A combined untargeted and semi-targeted LC-MS/MS metabolomics approach identified a distinct SI metabolic footprint, with bile acids and amino acids being the most abundant classes of metabolites. Host and host/microbe-derived bile acids were particularly abundant in SI samples. The application of a fast culturomics approach to two SI samples enabled species-level characterization, resulting in the identification of 90 bacterial species, including five potential novel species. The present study demonstrates the efficacy of our novel sampling MD in enabling comprehensive SI microbiome analysis through an integrative multi-omics approach, allowing the identification of distinct microbiome signatures between SI and fecal samples.

Preclinical and clinical studies have shown that molecular hydrogen (H2) has anti-oxidant, anti-inflammatory, and anti-apoptotic properties. Safety data are available in the literature and acute toxicity has been tested in isolated cells and laboratory animals. We have evaluates the genotoxicity of H2 in vivo in rats after 72 h exposure, following the International Council for Harmonization guidelines ICH S2 (R1). The study was conducted on three groups of male Wistar rats: a negative control group, a positive control group receiving methyl methanesulfonate, and a H2-treated group receiving a 3.1% H2 gas mixture for 72 h. Alkaline comet, formamidopyrimidine DNA glycosylase (Fpg)-modified comet and bone marrow micronucleus assays were performed. H2 exposure increased neither comet-tail DNA intensity (DNA damage) nor frequency of "hedgehogs" in blood, liver, lungs, or bronchoalveolar lavage fluid. No increase in Fpg-sensitive sites in lungs, no induction of micronucleus formation, and no imbalance of immature erythrocyte to total erythrocyte ratio (IME%) was observed in rats exposed to H2. The ICH S2 (R1) test-battery revealed no in vivo genotoxicity in Wistar rats after 72 h inhalation of a mixture containing 3.1% H2.

Background. Due to its antioxidant, anti-inflammatory, anti-apoptosis, and anti-fatigue properties, molecular hydrogen (H2) is potentially a novel therapeutic nutrient for patients with coronavirus acute disease 2019 (COVID-19). We determined the efficacy and safety profile of hydrogen-rich water (HRW) to reduce the risk of COVID-19 progression. Methods: We also conducted a phase 3, triple-blind, randomised, placebo-controlled trial to evaluate treatment with HRW initiated within 5 days after the onset of signs or symptoms in primary care patients with mild-to-moderate, laboratory-confirmed COVID-19. Participants were randomised to receive HRW or placebo twice daily for 21 days. The incidence of clinical worsening and adverse events were the primary endpoints. Results: A total of 675 participants were followed up to day 30. HRW was not superior to placebo in preventing clinical worsening at day 14: in H2 group, 46.1% in the H2 group, 43.5% in the placebo group, hazard ratio 1.09, 90% confidence interval [0.90–1.31]. One death was reported at day 30 in the H2 group and two in the placebo group at day 30. Adverse events were reported in 91 (27%) and 89 (26.2%) participants, respectively. Conclusions: HRW taken twice daily from the onset of COVID-19 symptoms for 21 days did not reduce clinical worsening.

Introduction: The Covid-19 pandemic, caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has triggered a serious global health crisis, resulting in millions of reported deaths since its initial identification in China in November 2019. The global disparities in immunization access emphasize the urgent need for ongoing research into therapeutic interventions. This study focuses on the potential use of molecular dihydrogen (H2) inhalation as an adjunctive treatment for Covid-19. H2 therapy shows promise in inhibiting intracellular signaling pathways associated with inflammation, particularly when administered early in conjunction with nasal oxygen therapy. Methods: This Phase I study, characterized by an open-label, prospective, monocentric, and single ascending dose design, seeks to assess the safety and tolerability of the procedure in individuals with confirmed SARS-CoV-2 infection. Employing a 3+3 design, the study includes three exposure durations (target durations): 1 day (D1), 3 days (D2), and 6 days (D3). Results: We concluded that the Maximum Tolerated Duration is at least three days. Every patient showed clinical improvement and excellent tolerance to H2 therapy. Discussion/conclusion: To the best of our knowledge, this phase 1 clinical trial is the first to establish the safety of inhaling a mixture of H2 (3.6%) and N2 (96.4%) in hospitalized Covid-19 patients. The original device and method employed ensure the absence of explosion risk. The encouraging outcomes observed in the 12 patients included in the study justify further exploration through larger, controlled clinical trials. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT04633980 ### Clinical Protocols ### Funding Statement The H2COVID study was supported by AirProducts which kindly provided the cylinders with the gas mixture and the administration device. It was carried out at CHU Grenoble Alpes (Grenoble University Hospital, France). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by French National Agency for Drug Safety and has been approved by a personal protection committee (SUD MED IV) on November 10th 2020 (Reference : 20 10 12-covid), following french regulation. Ethical approval was given. The clinical trial is available on clinicaltrials.gov with identifier [NCT04633980][1]. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04633980&atom=%2Fmedrxiv%2Fearly%2F2024%2F03%2F19%2F2024.03.15.24304071.atom

Robot-assisted Single Port (SP) surgical systems have become popular in laparoscopy, consisting of multiple flexible instruments and an endoscope emerging through a single cannula. This innovative approach presents several challenges related to a smaller workspace and visual field of view. Previous works on Dual-Arm Concentric Tube Continuum Robots (DACTCR) aimed to enhance SP systems by increasing autonomy in a specific surgical subtask, thus simplifying procedures and reducing the surgeon's workload. This paper extends beyond state-of-the-art methods, particularly the utilization of the relative Jacobian and null-space projection for cooperation control. The main contributions of this paper in simulation involve the incorporation of an actuation limit avoidance solution as an additional block to the DACTCR control system and the evaluation of different promising redundancy resolution techniques like saturation in the null-space and null-space projection, both formulated as constrained quadratic programming problems.

ABSTRACT The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has triggered a serious global health crisis, resulting in millions of reported deaths since its initial identification in China in November 2019. The global disparities in immunization access emphasize the urgent need for ongoing research into therapeutic interventions. This study focuses on the potential use of molecular dihydrogen (H2) inhalation as an adjunctive treatment for COVID-19. H2 therapy shows promise in inhibiting intracellular signaling pathways associated with inflammation, particularly when administered early in conjunction with nasal oxygen therapy. This phase I study, characterized by an open-label, prospective, monocentric, and single ascending-dose design, seeks to assess the safety and tolerability of the procedure in individuals with confirmed SARS-CoV-2 infection. Employing a 3 + 3 design, the study includes three exposure durations (target durations): 1 day (D1), 3 days (D2), and 6 days (D3). We concluded that the maximum tolerated duration is at least 3 days. Every patient showed clinical improvement and excellent tolerance to H2 therapy. To the best of our knowledge, this phase I clinical trial is the first to establish the safety of inhaling a mixture of H2 (3.6%) and N2 (96.4%) in hospitalized COVID-19 patients. The original device and method employed ensure the absence of explosion risk. The encouraging outcomes observed in the 12 patients included in the study justify further exploration through larger, controlled clinical trials. CLINICAL TRIALS This study is registered with ClinicalTrials.gov as NCT04633980 .

Background: Dihydrogen (H-2) is produced endogenously by the intestinal microbiota through the fermentation of diet carbohydrates. Over the past few years, numerous studies have demonstrated the significant therapeutic potential of H-2 in various pathophysiological contexts, making the characterization of its production in laboratory species of major preclinical importance. Methods: This study proposes an innovative solution to accurately monitor H-2 production in free-moving rodents while respecting animal welfare standards. The developed device consisted of a wire rodent cage placed inside an airtight chamber in which the air quality was maintained, and the H-2 concentration was continuously analyzed. After the airtightness and efficiency of the systems used to control and maintain air quality in the chamber were checked, tests were carried out on rats and mice with different metabolic phenotypes, over 12 min to 1-h experiments and repeatedly. H-2 production rates (HPR) were obtained using an easy calculation algorithm based on a first-order moving average. Results: HPR in hyperphagic Zucker rats was found to be twice as high as in control Wistar rats, respectively, 2.64 and 1.27 nmol.s(-1) per animal. In addition, the ingestion of inulin, a dietary fiber, stimulated H-2 production in mice. HPRs were 0.46 nmol.s(-1) for animals under control diet and 1.99 nmol.s(-1) for animals under inulin diet. Conclusions: The proposed device coupled with our algorithm enables fine analysis of the metabolic phenotype of laboratory rats or mice with regard to their endogenous H-2 production.

The need for personal protective equipment increased exponentially in response to the Covid-19 pandemic. To cope with the mask shortage during springtime 2020, a French consortium was created to find ways to reuse medical and respiratory masks in healthcare departments. The consortium addressed the complex context of the balance between cleaning medical masks in a way that maintains their safety and functionality for reuse, with the environmental advantage to manage medical disposable waste despite the current mask designation as single-use by the regulatory frameworks. We report a Workflow that provides a quantitative basis to determine the safety and efficacy of a medical mask that is decontaminated for reuse. The type IIR polypropylene medical masks can be washed up to 10 times, washed 5 times and autoclaved 5 times, or washed then sterilized with radiations or ethylene oxide, without any degradation of their filtration or breathability properties. There is loss of the anti-projection properties. The Workflow rendered the medical masks to comply to the AFNOR S76-001 standard as "type 1 non-sanitory usage masks". This qualification gives a legal status to the Workflow-treated masks and allows recommendation for the reuse of washed medical masks by the general population, with the significant public health advantage of providing better protection than cloth-tissue masks. Additionally, such a legal status provides a basis to perform a clinical trial to test the masks in real conditions, with full compliance with EN 14683 norm, for collective reuse. The rational reuse of medical mask and their end-of-life management is critical, particularly in pandemic periods when decisive turns can be taken. The reuse of masks in the general population, in industries, or in hospitals (but not for surgery) has significant advantages for the management of waste without degrading the safety of individuals wearing reused masks.

Supercritical Carbon Dioxide treatment of clean and soiled Filtering Face-Piece respirators is shown to meet mandatory requirements for safe reuse of FFP2. Preliminary tests enabled us to select optimal conditions for Supercritical Carbon Dioxide treatment of FFP2, for one hour at 343 K under 7.5 MPa, with a biocide solution. FFP2s from Paul Boye ' (R) were then tested before and after Supercritical Carbon Dioxide treatment with a soiling solution and a biological indicator (i.e. spores of GeoBacillus stearothermophilus) with respect to three objectives: (i) washing of organic deposits, (ii) sterilization (i.e. spores inactivation) and (iii) preservation of the filtration performances. The proposed Supercritical Carbon Dioxide treatment fulfils these three criterions, with effective decontamination of spores and promising washing preserving FFP2 requirements for filtration efficiency of aerosol ( 94%) with acceptable pressure drop (< 240 Pa). As a simple and low-cost one-step recycling method, Supercritical Carbon Dioxide fits to economical and sustainable development standpoints but also allows one to come back to good practices of face protective equipment use, lowering eventual shortage and tensions for most countries importing these respirators.

Analysis of kinematic and postural data of adolescent idiopathic scoliosis (AIS) patients seems relevant for a better understanding of biomechanical aspects involved in AIS and its etiopathogenesis. The present project aimed at investigating kinematic differences and asymmetries in early AIS in a static task and in uniplanar trunk movements (rotations, lateral bending, and forward bending). Trunk kinematics and posture were assessed using a 3D motion analysis system and a force plate. A total of fifteen healthy girls, fifteen AIS girls with a left lumbar main curve, and seventeen AIS girls with a right thoracic main curve were compared. Statistical analyses were performed to investigate presumed differences between the three groups. This study showed kinematic and postural differences between mild AIS patients and controls such as static imbalance, a reduced range of motion in the frontal plane, and a different kinematic strategy in lateral bending. These differences mainly occurred in the same direction, whatever the type of scoliosis, and suggested that AIS patients behave similarly from a dynamic point of view.

Reducing the radiation dose is a major challenge in the field of interventional radiology since it is often performed under continuous x-ray radiography (i.e. fluoroscopy). For the particular intervention of catheterization, a real-time 2D localization of the catheter tip on the image plane is required. A novel system called virtual fluoroscopy allows the 2D catheter tip localization with a dose reduction by several orders of magnitude compared to conventional fluoroscopy. Virtual fluoroscopy consists of placing a rotating slit collimator between the source and the patient, where the slit is away from the rotation axis and the resulting rotating fan-beam intersects the catheter tip two times per collimator rotation. The two intersection instants are measured with a miniaturized x-ray probe placed at the catheter tip, allowing to deduce the corresponding collimator orientation angles and then the 2D location of the catheter tip.With the aid of a simple geometric model, we provided an exact bound for the catheter tip 2D localization error according to the collimator angular position measurement accuracy, and the slit and point radii (the distances between the rotation axis and respectively the collimator slit and the catheter tip). In addition, we simplified the latter bound and deduced that the localization accuracy follows two distinct behaviors: it is linear with the collimator angular position measurement accuracy for small point radii (lower than $\sqrt 2$ times the slit radius) and quatratic for greater point radii.We performed a numerical application of the localization error bounds following the design of an existing prototype and, using simulated randomized collimator angular position measurement errors, verified that the 2D localization errors always remained lower than the computed exact bound.

Analysis of kinematic and postural data of adolescent idiopathic scoliosis (AIS) patients seems relevant for a better understanding of biomechanical aspects involved in AIS and its etiopathogenesis. The present project aimed at investigating kinematic differences and asymmetries in early AIS in a static task and in uniplanar trunk movements (rotations, lateral bending and forward bending). Trunk kinematics and posture were assessed using a 3D motion analysis system and a force plate. Fifteen healthy girls, fifteen AIS girls with left lumbar main curve and seventeen AIS girls with right thoracic main curve were compared. Statistical analyses were performed to investigate presumed differences between the three groups. This study showed kinematic and postural differences between mild AIS patients and controls such as static imbalance, a reduced range of motion in the frontal plane and a different kinematic strategy in lateral bending. These differences mainly occurred in the same direction whatever the type of scoliosis, and suggested that AIS patients behave similarly from a dynamic point of view.

Visceral congestion and edema are important features of advanced heart failure. Monitoring the evolution of fluid content in the gastric wall might provide an index of the development of this phenomenon and therefore constitute an innovative marker to early detect acute decompensated heart failure episodes. The evolution of the fluid content in the gastric wall is measured using a device implanted in the submucosa layer of the fundic region of the stomach. The device composed of two electrodes measures the bioimpedance values that reflects the water content of the tissue.An in-vivo experiment in a pig was carried out to validate the feasibility of detecting the gastric bioimpedance variations during the development of an experimental acute visceral edema caused by an endotoxemic shock. Our preliminary results confirm the possibility to monitor the bioimpedance variations due to moderate changes in tissue water content (10%) with a two-electrode configuration device implanted in the submucosa of the stomach.

The natural biodegradabilty of porous silicon (pSi) in physiological media limits its wider usage for implantable systems. We report the stabilization of porous silicon (pSi) membranes by chemical surface oxidation using RCA1 and RCA2 protocols, which was followed by a PEGylation process using a silane-PEG. These surface modifications stabilized the pSi to allow a long period of immersion in PBS, while leaving the pSi surface sufficiently hydrophilic for good filtration and diffusion of several biomolecules of different sizes without any blockage of the pSi structure. The pore sizes of the pSi membranes were between 5 and 20 nm, with the membrane thickness around 70 mu m. The diffusion coefficient for fluorescein through the membrane was 2 x 10(-19) cm(2) s(-1), and for glucose was 2.2 x 10(-9) cm(2) s(-1). The pSi membrane maintained that level of glucose diffusion for one month of immersion in PBS. After 2 months immersion in PBS the pSi membrane continued to operate, but with a reduced glucose diffusion coefficient. The chemical stabilization of pSi membranes provided almost 1 week stable and functional biomolecule transport in blood plasma and opens the possibility for its short-term implantation as a diffusion membrane in biocompatible systems.

Background: The coronavirus infectious disease-2019 (COVID-19) pandemic has led to an unprecedented shortage of healthcare resources, primarily personal protective equipment like surgical masks, and N95/filtering face piece type 2 (FFP2) respirators. Objective: Reuse of surgical masks and N95/FFP2 respirators may circumvent the supply chain constraints and thus overcome mass shortage. Methods, design, setting, and measurement: Herein, we tested the effects of dry- and moist-air controlled heating treatment on structure and chemical integrity, decontamination yield, and filtration performance of surgical masks and FFP2 respirators. Results: We found that treatment in a climate chamber at 70°C during 1 h with 75% humidity rate was adequate for enabling substantial decontamination of both respiratory viruses, oropharyngeal bacteria, and model animal coronaviuses, while maintaining a satisfying filtering capacity. Limitations: Further studies are now required to confirm the feasibility of the whole process during routine practice. Conclusion: Our findings provide compelling evidence for the recycling of pre-used surgical masks and N95/FFP2 respirators in case of imminent mass shortfall.