In the present matched-cohort study, we investigated the efficacy of olanexidine gluconate in comparison with chlorhexidine-alcohol as an antiseptic agent in thoracic esophagectomy.A total of 372 patients with esophageal cancer who were scheduled to undergo thoracic esophagectomy between 2016 and 2018 were assigned to one of two groups based on the preoperative antiseptic agent used in thoracic esophagectomy. We investigated the incidence of surgical site infectious complications in the propensity-matched cohort.p = 0.39/p = 0.03). Notably, the respective incidences of surgical site infection except anastomotic leakage were 1.7% and 7.0% in the olanexidine and chlorhexidine groups (p = 0.04).Based on the propensity score, 116 patients prepared with 1.5% olanexidine gluconate and 114 patients prepared with 1.0% chlorhexidine-alcohol as surgical skin antisepsis were selected. No significant intergroup differences were observed with respect to incisional surgical site infection (0.8% in the olanexidine group versus 0.8% in the chlorhexidine group) and deep fascial/organ space surgical site infection (1.7%/10.3% in the olanexidine group versus 3.5%/15.7% in the chlorhexidine group, Olanexidine gluconate was well tolerated and significantly reduced incidence of surgical site infection except anastomotic leakage in comparison with chlorhexidine-alcohol as an antiseptic agent in thoracic esophagectomy with three-field lymph node dissection. The use of optimal skin antiseptic agents is of critical importance, especially during traumatic surgical procedures , 2. One Staphylococcus aureus, vancomycin-resistant Enterococcus, Pseudomonas aeruginosa, and even Serratia marcescens compared with chlorhexidine [Olanexidine , containing 1.5% olanexidine gluconate, is a new skin antiseptic agent that was approved in Japan in 2015. This newly developed antiseptic agent is a biguanide disinfectant with a similar structure to chlorhexidine, with a wide range of antimicrobial activity. Olanexidine is particularly effective against methicillin-resistant hexidine , 8. Recehexidine . HoweverThis study was a retrospective, single-center, two-arm cohort study performed between 2016 and 2018 at the National Cancer Center Hospital East, Japan. Eligible patients were assigned to receive skin disinfection with either 1.5% olanexidine gluconate  or 1.0% chlorhexidine-alcohol  30 min before surgery, and 372 consecutive patients were analyzed. Written informed consent was obtained from all patients. The study was approved by the Committee for ethics of the National Cancer Center (Japan) . Also, this study confirms to the provisions of the Declaration of Helsinki (as revised in Tokyo 2004).Patients who underwent thoracic esophagectomy for esophageal cancer at the National Cancer Center Hospital East, Japan, were investigated. Preoperative diagnoses were based on imaging studies, including upper gastrointestinal studies, endoscopy, and conventional cross-sectional imaging (computed tomography). Histological evaluation of endoscope-guided biopsy specimens was performed in all cases. Data on the preoperative stage of the disease, histopathological findings, surgical procedures performed, and outcomes were collected from the patient medical records, as described previously .In all cases, thoracic esophagectomy was performed under the direction of the regular attending surgeon. For transthoracic esophagectomy, subtotal resection of the esophagus was performed with three-field regional lymph node dissection, regardless of the tumor stage. In the thoracoscopic approach, we preserved the azygos arch and the right bronchial artery. In contrast, the azygos arch was transected in all patients who underwent the thoracotomy approach. The laparoscopic approach was principally used, except in cases with bulky lymph node metastasis or previous history of abdominal surgery via laparotomy. The esophagus was usually reconstructed with a gastric tube via the retrosternal route; right hemi-colic reconstruction was performed via the posterior sternal route when gastrectomy of the remnant stomach was required, as described previously .The standard institutional anesthetic practice for thoracic esophagectomy was modified to enable the development of intraoperative core hypothermia in the present study. In brief, upon patient arrival in the operating room, routine monitoring was applied, which included electrocardiography, noninvasive blood pressure monitoring, pulse oximetry, and capnography. Before the induction of anesthesia, an epidural catheter was inserted at the fifth to sixth thoracic interspace, and placed 5 cm beyond the introducing needle tip, as described previously .Anesthesia was induced with 1.5–2.5 mg/kg propofol, 1–2 μg/kg fentanyl, and 0.1 mg/kg vecuronium. Anesthesia was maintained with 3% end-tidal sevoflurane in oxygen until tracheal intubation. Anesthesia was then maintained with 2% end-tidal sevoflurane at 40% oxygen (air/oxygen mixture at 4 L/min) supplemented with doses of fentanyl and vecuronium. A heat- and moisture-exchanging filter was positioned between the endotracheal tube and the breathing circuit, as described previously .4/mm3 or leukopenia of < 4 × 103/mm3, and signs of inflammation on auscultation, as described previously [SSI was judged in accordance with the definition established by the Surgical Wound Infection Task Force 1, and included infections at the incision site or organ/space manipulated during operative intervention. Remote infections were not included in the definition of an SSI, with the exception of bloodstream infections related to a SSI. Symptomatic remote infections were also included in the analysis. Among the remote infections, respiratory infection was defined as the presence of new or progressive infiltrates on chest radiographs, plus at least two of the following signs of respiratory tract infection: temperature > 38 °C, purulent sputum, leukocytosis of > 1 × 10Perioperative management was performed with the same clinical management pathway (CMP) for all patients, regardless of the type of abdominal approach, as described previously . All patPerioperative management was performed by the same clinical staff in the same environment using the ICU and subsequent ward-based facilities. The same principles of care were applied to both groups. The CMP was applied in both the ICU (POD 1 and 2) and the surgical ward (POD 3 and later). In brief, the endotracheal tube was removed from all patients in the operating room or immediately upon arrival in the ICU. Patients remained in the ICU for 1 day after surgery. On POD 6, a radiographic contrast agent swallow examination was performed to evaluate the anastomosis and any passage problems. If this examination showed no leakage or obstruction, the nasogastric tube was removed and oral intake was initiated in accordance with the postoperative diet program. In the absence of any complications, the patient was enrolled in the postoperative rehabilitation program and discharged on POD 12–20, as described previously .If there were any abnormal clinical findings such as hypoxia, leukocytosis, or abnormal pleural drainage during the course of the postoperative CMP, computed tomography and radiographic examinations were performed to diagnose and optimally manage the abnormality as soon as possible as described previously .p value < 0.05 was considered to indicate a statistically significant difference. All statistical analysis were performed using R calculation software.Propensity score matching was used to assemble two comparable groups. The covariates were preoperative treatment, thoracic surgical approach, abdominal surgical approach, clinical stage, ASA Grade, and type of antibiotics. Each patient in the olanexidine gluconate group was matched to a patient in the chlorhexidine-alcohol group who had the closest propensity score using simple 1:1 matching without replacement. To prevent poor matches, a caliper of 0.20 of the standard deviation of the logit of the propensity score was used. Intergroup differences were analyzed using the Chi-squared test and the Mann–Whitney U-test. A p = 0.81), incidence of anastomotic leakage , or in-hospital deaths (p = 0.95). The success rates of the CMP were similar in both groups .Of the 372 included patients, the antiseptic agent was chlorhexidine-alcohol in 178 patients, and 1.5% olanexidine gluconate in 194 patients. Olanexidine gluconate was well tolerated and no adverse events specific to its administration were observed. All patients were successfully treated using the CMP without any problems. There were no significant differences between the chlorhexidine-alcohol and olanexidine gluconate groups with respect to baseline patient characteristics, including age, sex, body mass index, ASA grade, preoperative treatment, and clinical stage of the disease before adjusting (Table p = 0.09), incidence of incisional or deep SSI . There were no difference in median postoperative hospital stay (p = 0.88). There were no in-hospital deaths in either group, and the success rates of the CMPs were similar in both groups . Notably, there was significant difference between groups in the incidence of all SSI with no association with anastomotic leakage   than other antiseptic skin agents, including chlorhexidine-alcohol or povidone iodine [p = 0.002), while there were no significant intergroup differences in the incidence of deep incisional SSI  [Olanexidine gluconate is a new antiseptic skin agent developed and approved in Japan. Olanexidine gluconate has antimicrobial activity against a wide range of bacterial species, including Gram-positive and Gram-negative bacteria , 14. Fure iodine , 8. Sevee iodine –17. A re = 0.06) ; therefoIt is widely recognized that there are several types of surgical procedures that have accompanying relatively high incidences of SSI in digestive surgery. Patients who undergo thoracic esophagectomy have a higher risk of SSI than those who undergo other types of digestive surgery , 20. In p = 0.13). Usually, patients who undergo preoperative treatment have a lower white blood cell count, which potentially makes them more vulnerable to bacterial infections [The present study has several limitations. First, this study was investigated retrospectively. A recent randomized control study revealed that olanexidine gluconate significantly reduces the occurrence of overall SSI and superficial incisional SSI compared with povidone iodine in clean-contaminated surgery . Therefofections . HoweverIn conclusion, present study firstly report the direct comparison between olanexidine gluconate and chlorhexidine-alcohol. The present results indicate that olanexidine gluconate as an antiseptic agent is effective for the prevention of surgical site infectious complications after thoracic esophagectomy with three-field lymph node dissection. Further analysis of a larger number of cases in a randomized controlled study would provide detailed results on the potential influence of olanexidine gluconate in thoracic esophagectomy.


Lynx pardinus) is one of the most endangered felid species in the world. Conservation efforts have increased its population size and distribution and reinforced their genetic diversity through captive breeding and reintroduction programmes. Among several threats that the Iberian lynx faces, infectious and parasitic diseases have underlined effects on the health of their newly reintroduced populations, being essential to identify the primary sources of these agents and assess populations health status. To achieve this, 79 fresh faecal samples from Iberian lynx and sympatric mesocarnivores were collected in the reintroduction area of Extremadura, Spain. Samples were submitted to copromicroscopic analyses to assess parasite diversity, prevalence, and mean intensity of parasite burden. Overall, 19  samples were positive for at least one enteric parasite species. Parasite diversity and prevalence were higher in the Iberian lynx (43.8%) compared with the others mesocarnivores under study . Ancylostomatidae and Toxocara cati were the most prevalent (15.6%) parasites. Obtained results revealed that Iberian lynx role as predator control might have reduced parasite cross-transmission between this felid and mesocarnivores due to their decreasing abundances. Surveillance programs must include regular monitoring of this endangered felid, comprising mesocarnivores, but also domestic/feral and wild cat communities.The Iberian lynx ( Lynx pardinus), an endemic species of the Iberian Peninsula, is considered one of the most threatened Felidae species in the world, listed as “endangered” by the IUCN Red List of Endangered Species [Oryctolagus cuniculus)—and infectious diseases are still threatening the survival and thrive of this species [Toxocara cati, Toxocara canis, Toxascaris leonina, Ancylostoma spp., Eucoleus aerophilus, Taenia spp., Hymenolepis spp., Mesocestoides sp.). Considering its potential impact on host physical condition and population stability, the study of parasite burdens is utterly essential for management and conservation purposes of Iberian lynx populations [The Iberian lynx , given the Iberian lynx’s aggressive behaviour towards other carnivores and well-established territories [Giardia duodenalis, Cryptosporidium spp., Enterocytozoon bieneusi, and Blastocystis spp. in mesocarnivore communities in overlap areas of the Iberian lynx presence, being crucial to assess and monitor the health status of both the Iberian lynx and sympatric species [As an apex predator, the restoration of this feline in areas of historical presence has had a negative impact on sympatric mesocarnivores densities  identify and determine the prevalence and intensity of the enteric parasitic fauna present in the recently reintroduced Iberian lynx population and the sympatric mesocarnivores community of Extremadura region; (ii) understand the potential of parasite cross-transmission between the mesocarnivore reservoirs and the Iberian lynx, as they belong to the same carnivore guild. To our knowledge, this is the first study performed, using conventional copromicroscopic methods, to assess the parasitic fauna in this newly reintroduced Iberian lynx population.Toxocara cati and Toxascaris leonina eggs were differentiated based on the size , colour, and structure: T. leonina presents a thick, smooth and colourless shell, with a yellowish-brown content that only occupies part of the shell, which differs from T. cati egg, which displays a thick, rough, and pitted shell with a dark brown content that occupies all the compartment; Trichuris sp. was identified based on its size (70–90 μm × 32–41 μm), lemon shape, transparent convex polar plugs, and thick shell with a smooth surface [Cystoisospora spp. oocysts were determined based on its elliptical shape, smooth, clear cyst walls, and the presence of a single, round cell (sporoblast) [Martes foina) sample analysed was also positive with one parasitic form. No enteric parasites were detected on the samples collected from the genet, the Eurasian otter (Lutra lutra) or the European badger (Meles meles). All the parasites found were identified with the Willis flotation technique, which is suitable to identify nematode eggs/coccidia oocysts like the ones we found. The same parasites were also found in the same parasitized samples after performing the sedimentation technique, even though this technique is normally used to identify trematode eggs. Most of the infections were monospecific, whereas mixed infections were only present in Iberian lynx samples, with a total of four (12.5%) samples presenting more than one parasitic form; two samples (6.3%) presented T. cati and T. leonina, and another two (6.3%) samples presented Trichuris sp., T. cati and Cystoisospora sp. oocysts. No L1 of lungworms nematodes were detected with the Baermann technique.From a total of 79 samples, 19  were infected with four different helminths and one protozoa . Helmintroblast) . In totap = 0.53).We did not find any significant differences for Ancylostomatidae, a parasite found in the Iberian lynx and another three mesocarnivores  , followed by Cystoisospora sp. (1250), both found in Iberian lynx samples. These EPG results show that the parasites present in Trichuris sp. which, to our knowledge, was the first description in this wild felid. Notwithstanding, Trichuris felis, Trichuris campanula, and Trichuris serrata were previously reported in cats [T. vulpis in several wild carnivores [Trichuris sp. in Iberian lynx as a pseudoparasitism event, acquired from the ingestion of an infected host, despite the high EPG found in one of the samples (200 EPG).All the parasites found in this study have been previously reported in Iberian lynx ,16,17,18 in cats ,26 and Trnivores . NonetheAncylostoma sp.  [T. cati, T. leonina, and Cystoisospora felis ).Previous studies recorded a higher prevalence of arbonell , 24.2% Aarbonell , and 57.arbonell ), compar (12.5%) , despitea et al.  reportedarbonell , 33.3% fCystoisospora canis was reported by Rodríguez and Carbonell [Ancylostoma sp. (5.0%). Other authors reported higher prevalence for Cystoisospora sp.  and for, 20.4%, ), than tce of 5% , and, to authors ,15,17,18Aelurostrongylus abstrusus, Oslerus rostratus, Angiostrongylus chabaudi, and nematodes of the genus Troglostrongylus in wild/domestic cats and other wild Felidae species [A. abstrusus was previously recorded in the Eurasian lynx (Lynx lynx) with a prevalence of 17% [No L1 of lungworms nematodes were detected in the Iberian lynx and mesocarnivores, even though previous studies have reported  species . A. abste of 17% .T. cati and Cystoisospora sp., but no infection rate was possible to calculate for Ancylostomatidae, which was previously reported by Vicente et al. [Ancylostoma sp. with a maximum of 21,195 EPG.Average intensity for EPG found on Iberian lynx was high, especially for e et al.  for AncyTrichuris sp., T. cati, T. leonina, and Cystoisospora sp. have direct life cycles , even though the last three agents can also adopt a facultative indirect life cycle (through the ingestion of infected paratenic hosts) [A. tubaeforme and T. cati). This may be an indicator of overlapping between sylvatic and domestic (or peri-domestic) transmission cycles of these parasites, as previously suggested by Barrera et al. [Cryptosporidium hominis found in red foxes in Galicia. Millán and Casanova [T. cati, which is more cat-specific, according to Ribas et al. [Overall, the prevalence and parasite richness found was somewhat lower than expected, especially in the mesocarnivore community, though the high infection rates found. The parasite Ancylostomatidae was the only one found in both the Iberian lynx and in three mesocarnivore species. Similar to this parasite, c hosts) . This mec hosts)  or even c hosts)  and Millc hosts)  previousa et al.  for the Casanova  found anCasanova  reporteds et al.  and Olmes et al. , most ofs et al.  also fous et al. . Even ths et al. , reducins et al. , affectis et al. , but alss et al.  or the ns et al. , but alss et al. .®, Zoetis Belgium SA, Louvain-la-Neuve, Belgium). Moreover, not only samples were obtained from reintroduced lynxes, since reproduction and wild-born individuals were recorded during the second and subsequent years of the program.The low prevalence and parasite richness found could not be explained by the administration of a topical parasiticide before release, not mentioning that it does not work on cestodes, since selamectin only shows activity over nematodes and arthropods. Although lynxes were treated before being reintroduced and may initially benefit from a lack of parasite burden, this effect only lasted for a short period, as the plasma clearance in the parasiticide used is 30 days and the elimination half-life after topical administration is around eight days in cats , red fox (8.1%), and wolf (17%), Cryptosporidium hominis in badger and C. felis and C. ubiquitum in red fox; Santín et al. [Enterocytozoon bieneusi in the European badger, stone marten, and red fox, in a total of 13.2% of the analysed samples; Calero-Bernal et al. [Blastocystis sp. found in samples of red fox, common genet, and European polecat); (3) the lack of samples in this study from domestic/feral and wild cats, as previously mentioned, may have decreased the total prevalence found, given their host specificity and transmission cycles, favouring disease transmission between domestic animals and wildlife and increasing disease risk for the Iberian lynx [Eimeria sp. oocysts in three samples of Iberian lynx, which corroborate the need to account in similar future studies herbivore species, given their important role as intermediate hosts of parasites with complex life cycles.It is essential to highlight this study’s main limitations, which may be another of the reasons behind the overall low diversity, prevalence, and intensity found: (1) the relatively small sample size and the low number of positive samples made it challenging to conduct statistical analyses and hamper obtaining robust conclusions ; (2) the conventional microscopy-based nature of the study may have underestimated the true prevalence of the investigated parasites (particularly protist species), as microscopy is less sensitive than molecular techniques (PCR and sequencing). Previous studies carried out with meso and apex carnivores reported different protist species and prevalence in several regions of Spain  Even though a small portion of the faecal samples we obtained were through routine check-ups, post-mortem examinations, and road-killed incidents, our sampling was predominantly non-invasive, based on the collection of fresh samples in the environment. This methodology is, however, suitable for wildlife studies, especially when we are working with endangered species/populations, such as the Iberian lynx individuals that inhabit Extremadura. Thus, it is imperative to better understand parasites’ true impacts in the ecosystem and their interactions with different organisms to provide additional information to minimise parasitic transmission and outbreaks especially in endangered populations . ConsideErica spp., Cistus spp., and Rosmarinus spp.) and dense scrub , but also open pasture areas. This kind of habitat frequently supports high densities of rabbits, representing 80–99% of Iberian lynx diet [This study was conducted in Hornachos-Matachel Valley  , a studyynx diet , since iynx diet . Aside fynx diet .Chlamydophila felis . Additionally, a topical parasiticide, selamectin , was administered. All lynxes were radio-collared. Lynxes (reintroduced and wild-born) that were subject to capture after being released  received a booster of feline leukaemia virus vaccine and depending on ectoparasite  loads, fipronil  was administered topically. For the purpose of this study, between February 2016 and July 2018, 79 fresh faeces were collected from Iberian lynx (n = 32), red fox (n = 21), Egyptian mongoose (n = 18), common genet (n = 3), Eurasian otter (n = 3), European badger (n = 1), and stone marten (n = 1). Samples were collected during routine check-ups/live-capture operations, post-mortem examinations, road-killed incidents, and by prospecting animals’ latrines in several well-distributed transects across the study area , establishing confidence limits within 95% confidence intervals (CI). The intensity of the infection was estimated as the mean number of parasite eggs/oocysts per infected hosts [www.r-project.org) to assess significant differences between parasitic prevalence found in the Iberian lynx and at least one mesocarnivore, for a p-value ≤ 0.05.Parasite prevalence was calculated based on Bush et al. , as the ed hosts , using ted hosts . The χ2-The implementation of wildlife disease surveillance programs is crucial for conservation purposes and will allow the identification of disease hotspots to minimise parasitic transmission and outbreaks in the recently reintroduced lynx populations. We suggest that this surveillance programs must include regular monitoring protocols in all Iberian lynx territories of the Iberian Peninsula, comprising the sympatric mesocarnivores communities, but also including domestic/feral cats, and applying, if necessary, preventive or corrective measures.


OBJECTIVES/GOALS: Haptoglobin (Hp) phenotypes may affect inflammatory response after neurologic injury. We are investigating the relationship between patient Hp phenotypes and inflammatory cytokine concentrations in plasma and CSF after aneurysmal subarachnoid hemorrhage (aSAH), a severe form of hemorrhagic stroke. METHODS/STUDY POPULATION: Following IRB approval, all patients with angiographically-proven aSAH and who underwent extraventricular drain (EVD) placement were included. Patients were excluded if they were not expected to survive hospitalization or were on pre-existing anti-inflammatory agents. For all enrolled patients, plasma and CSF samples were taken on post-bleed days 3, 5, 7, and 10, processed and then frozen for later analysis. In this interim analysis, Hp phenotype was assessed through ELISA analysis of plasma samples and cytokine concentrations were determined using multiplex ELISA kits for both plasma and CSF samples. Hp phenotypes were dichotomized to either HP1 (Hp 1-1 or 1-2) or HP2 (Hp 2-2). RESULTS/ANTICIPATED RESULTS: To date, 23 aSAH patients have been enrolled in this IRB-approved study. An interim analysis of the first 13 patients has revealed eight Hp1 patients  and five Hp2 patients. CSF levels of IL-6 and TNF-a were greater than plasma levels in all patients at all time points. CSF levels of IL-6 appear to peak on PBD 5 (1890 ± 767 pcg/mL) and 7 (1612 ± 899 pcg/mL). The CSF IL-6 concentrations in the Hp2 group were lower (1792 ± 806 pcg/mL vs. 1952 ± 791 pcg/mL) on PBD5 but were higher (1635 ± 930 pcg/mL vs 1598 ± 943 pcg/mL) at PBD7; however, these differences did not reach statistical significance. DISCUSSION/SIGNIFICANCE OF IMPACT: This interim analysis demonstrated no statistically significant differences in plasma or CSF cytokine concentrations between patients with different Hp phenotypes. This may be due to the low number of samples or the potential confounding effect of disease-specific secondary neurological injuries.


The human brain functions at the center of a network of systems aimed at providing a structural and immunological layer of protection. The cerebrospinal fluid (CSF) maintains a physiological homeostasis that is of paramount importance to proper neurological activity. CSF is largely produced in the choroid plexus where it is continuous with the brain extracellular fluid and circulates through the ventricles. CSF movement through the central nervous system has been extensively explored. Across numerous animal species, the involvement of various drainage pathways in CSF, including arachnoid granulations, cranial nerves, perivascular pathways, and meningeal lymphatics, has been studied. Among these, there is a proposed CSF clearance route spanning the olfactory nerve and exiting the brain at the cribriform plate and entering lymphatics. While this pathway has been demonstrated in multiple animal species, evidence of a similar CSF egress mechanism involving the nasal cavity in humans remains poorly consolidated. This review will synthesize contemporary evidence surrounding CSF clearance at the nose-brain interface, examining across species this anatomical pathway, and its possible significance to human neurodegenerative disease. Our discussion of a bidirectional nasal pathway includes examination of the immune surveillance in the olfactory region protecting the brain. Overall, we expect that an expanded discussion of the brain-nose pathway and interactions with the environment will contribute to an improved understanding of neurodegenerative and infectious diseases, and potentially to novel prevention and treatment considerations. The highly coordinated function of the human brain in regulating nearly all bodily functions entails a fundamental need to protect its anatomical and functional homeostasis. The nose-brain interface, modulating a critical exchange between the nervous system and the environment, plays a role in immune function and fluid clearance. Serving as a primary physical boundary against the ready invasion of the central nervous system (CNS) by pathogenic organisms, the nasal region mediates a physiological safeguard of the brain. Alongside its regulation of environmental microbes, the nose-brain connection also functions in Cerebrospinal Fluid (CSF) circulatory pathways as demonstrated across numerous species. CSF flow, widely accepted to be driven by arterial pulsations that provide a pumping force, facilitates the removal of metabolic byproducts, toxic macromolecules, and other important substances . Its clevia the nasal-nervous pathway in many mammals, the anatomy and physiological significance of this pathway in humans remain largely unclear. This review, aimed at directly examining the importance of in-vivo and post-mortem human studies, explores the potential physiological relevance of the CSF clearance pathway mediated by the nose-brain interface.Among these clearance mechanisms, the scientific documentation of an olfactory pathway dates back to the 19th century and marks one of the earliest described CSF efflux avenues . Considevia filtration through the capillary walls into the extracellular space of the surrounding brain tissue  into the cisterna magna. In the CSF, EB remains unbound to proteins and can act as a low-weight molecular tracer transported by fluid convectional pathways. Permeation of EB into the nasal lymphatic system provides evidence for drainage of CSF through the cribriform plate (CP) in mice . Enrichea the CP . Howevera the CP .131I-Human Serum Albumin (HSA) into the cisterna magna resulted in an increased radioactivity within the nasal mucosa, nasal conchae, and nasal septum, reinforcing the view of a cribriform mediated nose-brain connection, predominant in fetal and neonatal life  must be used for the proposed existence of a similar connection in humans.In a series of tracer-based cadaveric studies, Johnston et al. investigated nasal CSF outflow in monkeys, mice, rats, pigs, and humans using yellow MicroFil injections into the subarachnoid space. Following infusion of the tracer, overall, the findings displayed a circulation of MicroFil into the nasal region across species, and tracer was detected in both the nasal mucosa and nasal turbinates . While tPerhaps, the most significant uncertainty of the olfactory drainage route for CSF in humans revolves not around its anatomical existence, but rather the extent to which this pathway is utilized. In a variety of animal models, passage through the cribriform plate and into the lymphatic system of the nasal mucosa defines a major pathway for CSF efflux. In sheep, for example, mathematical analysis of intracranial pressure after blocking the cribriform plate allows for an estimation of the fraction of CSF that proceeds through a nasal elimination route . Similarvia an olfactory path in humans may provide an explanation for the difficulty experienced in visualization and quantification of CSF traversing the cribriform plate into nasal lymphatics (see below). Emerging as an extension of work based on various animal models, the significance of a human nasal clearance route remains fundamentally unsolved.The cribriform plate-mediated drainage pathway found in many animals is a major but variable route of CSF drainage. An exact assessment of the proportional flow of CSF through nasal lymphatics in humans, however, remains unknown. A significantly less pronounced fraction of CSF cleared via one-way valves (Pacchionian (arachnoid) granulations) penetrating the dura and delivering CSF and ISF to circulating venous blood. This absorption along arachnoid granulations was believed to be along the superior sagittal sinus , and abnormalities of this system are believed to underlie conditions, such as normal pressure hydrocephalus (See “Human Pathology”). Classically, the elimination of CSF in the human was believed to be nus SSS;  and spinnus SSS; . More revia dural lymphatics . These studies also included one human sample . Here, fin-vivo imaging studies that physiologically demonstrate the importance of the anatomical pathway.Overall, the results from multiple post-mortem studies provide evidence for the clearance of Human CSF across the cribriform plate and into the nasal mucosa and cervical lymphatic circulation. Despite this, post-mortem work fails to adequately model the pressure dynamics and cellular mechanics of fluid flow that contribute to CSF outflow pathways of living humans. The importance of steady-state pressure equilibria on fluid dynamics, active cellular and vascular processes on CSF movement, and undeniable changes to histology following death are unaccounted for in these post-mortem examinations. On an experimental level, the technique of pushing contrast agents under abnormal pressure conditions in post-mortem samples leaves open the question of whether these studies can accurately assess CSF movement and pathways in living humans. Ultimately, while these cadaveric observations may suggest the possibility of CSF egress through the nasal region into the lymphatic system, they must be confirmed by in-vivo examination utilized MRI with time-of-flight angiography sequences to elucidate the directionality of flow within meningeal lymphatic vessels (MLV) running alongside the SSS. A coronal section anterior to the vertex of the skull was used to image meningeal lymphatic vessels running parallel the SSS. The results for the six participants examined indicated CSF flow in MLV was countercurrent to venous flow along the SSS  that utilize a variety of tracers that can monitor the flow of CSF as it circulates, and precisely address the pathways by which it clears.While the exploration of lymphatic drainage , counterin-vivo imaging studies that attempt to clarify the flow of CSF across the cribriform plate in humans.Extended to humans, MRI tracing of CSF bulk flow using intrathecally administered gadobutrol, a low-molecular weight contrast agent that can help monitor CSF flow in real time, displays direct involvement of the parasagittal dura, further suggesting a connection between dural lymphatics and CSF flow along the subarachnoid space . Recent 18F-THK5117, an intravenously administered tau pathology tracer . Using an ELISA assay and Western blotting analysis, anti-protein expression of IgG and IgA against S. Pneumoniae was found to be boosted in nasal wash after intranasal application of S. Pneumoniae, suggesting that the adaptive immune system is of importance to the environment-nose-brain interface , an established CSF-leak marker (PMID: 27614217). Although the animal models provide a reliable, accessible, and ethically sound means of assessing the structural pathways of CSF movement, they fail to encapsulate the physiology of human CSF outflow. In-vivo human studies become paramount. Understanding the role of the nose-brain connection in clearance of CSF from the nervous system may provide diagnostic assistance in infectious disease, NPH, CSF leaks, and age-related neurodegenerative diseases. Ultimately, the broadening scope of physiological research will continue to allow us to better understand the importance of the nose-brain connection to CSF clearance mechanisms in humans.The evidence for an olfactory route of clearance in humans began as an extension of the prevalent understanding of CSF fluid dynamics in animal models, progressed into post-mortem evaluations and now revolves around various n humans . UnderstNHM and MDL conceptualized the review. NHM is the principle author of the manuscript. All authors are contributing authors. MDL is the corresponding author for this review.This review was partially supported by the following research grants: R01 AG12101, R01 AG022374, R01 AG13616, RF1 AG057570, R56 AG058913-MdeL., R01AG068398-GCC., R56 NS111052-TB, and-R01 AG057848-YL. KB is supported by the Swedish Research Council (#2017-00915), the Swedish Alzheimer Foundation (#AF-742881), Hjärnfonden, Sweden (#FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986), and the Alzheimer’s Association 2021 Zenith Award (ZEN-21-84849).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


This scale actually brings the raw sEMG data, initially sampled at 10 kHz, to the specific 0–500 Hz sEMG spectral band of interest, which finally reveals the inner complexity of the data. This study promotes good practices in the use of MPE complexity measures on real data.Surface electromyography (sEMG) is a valuable technique that helps provide functional and structural information about the electric activity of muscles. As sEMG measures output of complex living systems characterized by multiscale and nonlinear behaviors, Multiscale Permutation Entropy (MPE) is a suitable tool for capturing useful information from the ordinal patterns of sEMG time series. In a previous work, a theoretical comparison in terms of bias and variance of two MPE variants—namely, the refined composite MPE (rcMPE) and the refined composite downsampling (rcDPE), was addressed. In the current paper, we assess the superiority of rcDPE over MPE and rcMPE, when applied to real sEMG signals. Moreover, we demonstrate the capacity of rcDPE in quantifying fatigue levels by using sEMG data recorded during a fatiguing exercise. The processing of four consecutive temporal segments, during  Electromyography is a relevant technique for providing functional and structural information about neuromuscular activities . This teThe sEMG signal genesis consists of the activation of a large number of elementary functional entities called motor units (MU) . A MU isMU activation is performed by a variety of motor units action potential (MUAP)  with difNumerous works using the sEMG technique have focused on changes in neuromuscular control in relation to the study of fatigue ,12. HoweIt is therefore interesting to evaluate more thoroughly and precisely the level of sEMG complexity by means of complexity-based measures. The entropy-based complexity measures have proven to be efficient tools for addressing complexity of such signals ,15,16,17In , a studyAs an alternative to PE, the multiscale permutation entropy (MPE)  is a PE-Numerous PE variants that explore multiscaling were introduced in the literature, including refined composite downsampling PE (rcDPE)  and refibiceps brachii during a fatiguing static isometric contraction exercise. As the theoretical study presented in  and the noise band . This ratio is 29.5 dB, which highlights a negligible noise level compared to power of the sEMG spectral band of interest. Therefore, the spectral aliasing due to the downsampling with In order to numerically support this claim, we evaluated the power ratio defined as the ratio between the integrated PSD in the Based on this, and since the downsampling with biceps brachii fatigue study at a static isometric 70% MVC contraction level, we recommend the use of a time scale that adjusts the coarse (or downsampled) signals close to 1000 Hz with at least an embedding dimension close to The link to the spectral analysis theory is, therefore, of high importance for an informed and correct interpretation. As a general rule of thumb when working with sEMG signals in the context of a d and m and for rcMPE and cMPE) will not be standard and will depend on the particular characteristics of the dataset and the application domain. They should be adjusted until a maximum difference between groups is reached, provided that Shannon’s theorem is respected. Notably, the recommendation is to limit the observed data inside their full frequency band of interest in order to achieve higher sensitivity with the rcMPE or rcDPE methods.Generally, these PE parameter values  for characterizing the complexity behavior of EMG signals.biceps brachii voluntary static contraction maintained at 70% of MVC until exhaustion.The rcDPE, which theoretically exhibits the smallest bias and variance with uncorrelated noise signals according to , performm = 10 value at which the rcDPE variations were the highest. This scale value is equivalent to down-sampling data from 10 to 1 kHz leading to the conclusion that limiting the observed data in their frequency band of interest  provides higher sensitivity. Moreover, the changes in the entropy values as a function of fatigue level that we observed are in agreement with the existing literature dedicated to fatigue studies [Most importantly is the scale  studies .From our findings, we can make some recommendations for the general use of multiscale entropy estimators in the frame of sEMG fatigue studies: The rcDPE method is recommended because it cancels correlation artifacts introduced by the coarse-graining procedure of multicale procedure. The choice of the We thus propose researchers follow these guidelines that promote good practices in the use of MPE complexity measures. The final objective is to correctly and better exploit the potential of such measures in letting real data express their inner complexity. Lastly, the biological interpretation of the time scale deserves further comments.We know the information content inside sEMG lies in the range of 20–500 Hz , which iThis study can be extended to other entropy estimators with refined composite downsampling versions in order to cancel the artificial correlations between composite signals introduced by to the composite coarse graining procedure independently of the natural autocorrelation of the data. The behaviors of these entropy estimators to composite downsampling procedures are worthy of study in this experimental frame.


This paper presents a novel weld groove parametrization algorithm, which is developed specifically for weld grooves in typical stub and butt joints between large tubular elements. The procedure is based on random sample consensus (RANSAC) with additionally proposed correction steps, including a corner correction step for grooves with narrow root weld, and an iterative error elimination step for improving the initially obtained data fit. The problem of curved groove sides (due to the pipe geometry) is attributed and solved. In addition, the procedure detects and eliminates several types of data noise due to laser line reflections. The performance of the procedure is studied experimentally using small-scale test objects, which have been ground using typical industrial power tools to achieve a realistic level of reflections. The execution times and data fit errors of the proposed procedure are compared to a procedure based on a more conventional RANSAC approach for line segment detection. Welding is an important manufacturing process for steel components and structures. Welding is often done by manual labor, especially for complex welding processes, complex interface geometries, and welds with high quality requirements. Alternatively, welding automation using robotic arms  can be used for products welded at factories. Robotic welding is relatively easy to implement for production lines with standard products with known geometry and small welds with few beads in the weld cross-section. However, robotic welding becomes more challenging when large components have to be welded together. This is due to larger geometrical deviations of components and large welds required to connect them. In such applications, scanning and parametrization of weld grooves is a vital step before welding can start. In this work, we propose an algorithm for precise parametrization of weld grooves at interfaces between large tubular joints when a 2-dimensional (2D) laser scanner is used.Various types of sensors can be used in robotic welding. The common application areas are seam tracking, weld pool monitoring, quality inspection, weld position identification, and groove geometry extraction. When the set of parameters in the extracted features is sufficient to describe a weld groove section uniquely, then the process of feature extraction can also be referred to as weld groove parametrization. Typical sensor technologies are ultrasound sensors , infrareComputer vision sensors are often used for weld groove (or weld seam) tracking, feature extraction, or groove geometry parametrization. Although, in some applications, analysis of global 3-dimensional (3D) point clouds ,8,9 or pLine laser triangulation sensors are a type of structured light sensors where the projected light is a line. Such sensors can scan one weld groove section at a time. The groove parametrization task can then be defined as a replacement of all scanned data points with a small set of parameters. One reasonable set of such parameters are the coordinates of corner points in the groove section . A simplWhen weld grooves in large tubular joints are scanned and parametrized, two main joint types should be taken into consideration. These are butt joints with a typical V-groove and stub joints (or T-joints) with an asymmetric weld groove with one side being curved (due to the pipe geometry) . The onlCommonly, weld grooves are ground before welding, which means that the groove steel surface can be very reflective, and the groove parametrization algorithms have to be able to handle some data noise. When laser triangulation sensors are used, noise can be handled at two levels: the camera image level and the point cloud level . If therAlthough a lot of research has been done on weld groove (or weld seam) parametrization , most of the research has dealt with V or U-grooves. In addition, little attention had been paid to the cases with strong surface reflections and high levels of data noise. In this paper, we propose a novel procedure for parametrization of weld grooves commonly used in stub or butt joints of large tubular elements. The algorithm takes a triangulated 2D point cloud from a commercial line laser sensor as an input and returns the corners points of a groove. The proposed procedure is based on a RANSAC search, where we propose several additional correction steps to obtain a better data fit and enable effective performance for grooves with narrow root welds. The procedure can also detect some forms of data noise caused by laser line reflections on the ground steel surface. The advantage of the procedure is that it does not require prior knowledge about the groove geometry, and it is faster than the conventional RANSAC approaches for groove parametrization. The procedure is directly applicable to commercial laser triangulation sensors (where raw image data might not be available), which facilitates easier industrial implementation.The rest of this paper is organized as follows. The system under consideration is a commercial line laser triangulation sensor and several different steel test objects with a weld groove between the plates, see The sensor used in the tests is the Micro-epsilon scanCONTROL 2610-100 (produced by MICRO-EPSILON MESSTECHNIK). The sensor has a 658 nm red laser with 8 mW power output. The default settings are used without the pre-programmed cross-section templates. The output of the sensor is an array of 640 points in a), (b)  and the second arrangement is typical for butt joints (c) between large pipes, see The test objects are steel plates  welded together with different widths of the root welds and two different plate arrangements. The thickness of the flat plates is 22 mm and the thickness of the cylindrical plates is 20 mm, while the radius of the cylindrical plates is 600 mm. The material of the plates is S420G2+M according to EN 10225:2009. This is a typical material of tubular elements used for production of offshore jacket structures. The test objects are made to represent typical sections of tubular stub and butt joints. The first arrangement is typical for stub joints (a) and (b) have different root conditions: from no root weld to step-wise increasing root weld. The test object (c) covers the cases with no root weld and a small (one weld pass) root weld. The scope of this work is limited to the cases with a ready-made root weld or with a backing weld, i.e., without a gap between plates. In practice, the root weld for very large pipes is expected to be welded manually due to large deviations in the pipe fit. Such root welds are preferred to be as small as possible (preferably one weld pass), but due to the larger gaps, they can require several weld passes, leading to wider root welds. Therefore, weld grooves with several different root weld widths are tested in this work.The test objects are ground similarly as they are in industrial situations, using the same type of power tools. The weld groove in the test objects . The examples of point sets are given in l asl to Frame k [k, is defined asThe set  can be e Frame k . The setThe point set i  2D groove profile and a V-groove profile from a butt joint. A typical model describing a groove profile with a root weld is shown in i consists of the corner points A weld groove The segment points for a butt joint groove are defined similarly.The corner detection method presented in this section is a three-step algorithm. In the first step, the sequential RANSAC procedure for finding line segments is implemented. This gives a roughly good fit, which has varying quality due to the random nature of RANSAC. In the second step, after each completed RANSAC search, it is checked if a found segment has assigned corner points belonging to the next segment; if so, those points are removed, and the segment is updated. An assigned point is a point defined as an inlier of the current segment and is removed from the remaining points of the dataset. In the third step, an iterative error elimination algorithm is implemented for the entire groove profile model. This step provides the final correction of the RANSAC fit.The sequential RANSAC for detecting line segments from the sensor data is implemented utilizing the expected data structure. Specifically, we use the fact that all line segments should be sequentially connected and each point from the dataset has a unique The procedure starts by assigning a start point for the first segment The segment is then defined by the first and the last points in the inlier set, where the inliers after the first detected gap along the g,in see  larger ti is compared to the direction vector i and The direction vector i and i is reset as If the angle assigned to that line segment. The assigned points are removed from the overall dataset and will not be used in the further segment search.All points in the set of inliers attributed to a certain line segment can be referred to as points i is being found. Then there are some points belonging to segment i due to the inlier tolerance i can cause problems searching segment i are returned to the overall dataset. The procedure is graphically demonstrated in Consider a line segment i is found , producing light pollution around the true laser line projection, see This light pollution causes difficulties for the sensor algorithm to identify the true laser line projection, and, therefore, such line pollution is referred to as noise in this work. The noise causes the data points to deviate from their true locations in the final 2D data output of the sensor. Such noise is rather difficult to predict, since it varies depending on the scanned surface finish and the geometry of the groove. However, arrays of consequent noisy points in most of the cases have different geometrical structures, comparing to the noise-free points. In this subsection we propose several metrics y-gap between the points, and the condition is given asy-gap size inconsistency is defined asThe first noise detection check is based on the maximum relative The noise detection checks are performed over a set of consequent points If the noise is detected in the set The iterative error elimination procedure for noisy data is essentially the same as described in It is worth noting that if the data contains a lot of noise, then the iterative error elimination procedure can result in divergence from the best-fit groove corner position. This happens due to a lack of data points, which gives a poor line fit. This means that the procedure should be avoided when very noisy data are analyzed.i, where i compared to the other segments , which was a relatively simple case. The scanned data were denoted as dataset 1. The dataset was of good quality with distinct sharp corners, which gave good groove parametrization results, see The blue corner dots in the graph show the result before the iterative error elimination procedure see  and the The mean execution time was measured to be 0.061 s, which gives above 16 scans per second. Provided that the entire weld needs to be scanned discretely every 20–30 mm along its length, such execution speed would allow for an approximate scanning capacity of 400 mm/s. Such scanning speed is several times above the practical scanning speed in the industry. The average point-to-segment error among all segments was within 0.034 to 0.070 mm, which was a very good segment-to-data fit. It is also notable that the maximum, minimum, and mean results were consistent over 10 algorithm runs due to the good quality of the scanned data.The next analyzed dataset (dataset 2) was obtained by scanning the groove with a 10 mm root, see The results showed a clear improvement of the groove parametrization after the iterative error elimination step, which is also reflected in The next test was performed for the groove with a 3 mm wide root weld (the dataset 3). Parametrization of grooves with a narrow root weld is a more complex task, since the algorithm can neglect the root by assigning its point as inliers to the neighboring groove sides. Therefore, the correction of assigned corners procedure see  was intrThe mean execution time was 0.126 s, which roughly corresponded to 200 mm/s available scanning speed. The point-to-segment errors were similarly low compared to the previous tests. To demonstrate the importance of the correction of assigned corners procedure, the results for datasets 2 and 3 without the correction step are presented in For the case with a 10 mm root, it is seen that the blue dots are located well after the corners. In that case, the iterative error elimination step corrected that error, moving the corner points to their realistic positions (the red dots). In the case with a 3 mm root (to the right), it is seen that the root segment was not detected at all, and the iterative error elimination procedure is not designed to correct such errors.The weld groove parametrization procedure presented in this work was originally developed for stub joints. In fact, the procedure is independent of the groove configuration. In this subsection we demonstrate that it can also be efficiently applied for the weld grooves in butt joints.The tests with a butt joint groove were performed for the case without root weld  and the case with 7 mm root weld, using datasets 4 and 5 see . The resThe execution times and average point-to-segment errors for 10 sequential runs are given in In this subsection, we study the performance of the algorithm using datasets with noise caused by reflections. The data noise caused by reflections can be different in structure and intensity, and can be located in different places. This depends on the surface treatment and laser pointing angle. In this work, we used test objects with surfaces machined using the same type of power tools as used in the industry, and the laser pointing angle was selected freely to obtain datasets with various types of noise. Data noise was classified into 3 different groups  depending on the noise location. The groups are described in the introduction to First, datasets 6 and 7 were analyzed, see The grey color in the graphs indicates the points identified as noise by the noise detection algorithm. The mean execution time was within 0.126 to 0.139 s, which was similar to the results using the noise-free dataset 3. The average point-to-segment error among all segments was within 0.039 to 0.258 mm, which was higher than the errors using the noise-free datasets. This could be explained by the minor noise, which was within the segment inlier tolerances and was not identified as noise by the noise detection algorithm. Such minor noise caused larger distances from the points to the found segment, which led to larger point-to-segment errors. It is also notable that the maximum and mean results were relatively consistent over 10 algorithm runs.The next datasets analyzed (datasets 8 and 9) were selected based upon their containing corner noise . The results showed that it was possible to identify the corner noise and locate the missing groove corner, see The two last noisy datasets (datasets 10 and 11) were selected to include the N3 noise, which is the noise inside the groove. The results are plotted in The N3 noise is different from the N1 and N2 types since it is mostly caused by the dominant part of spread reflections towards the other wall of the groove. This means that the noisy points are not necessarily located chaotically in the In this section a discussion on the advantages and disadvantages of the proposed procedure compared to the recently published methods is given. In addition, the proposed procedure is compared to a groove parametrization procedure based on the conventional RANSAC approach for line segment search.Recently, several methods have been proposed for weld seam tracking, where weld seam or weld groove parametrization (feature extraction) was a part of the procedure. In most of the proposed methods groove parametrization was done at the camera image level, i.e., using camera image points or pixels ,16,26,27Processing noisy data has been an important part of the recent developments. It is, however, worth noting that the recent methods have mostly been made for online seam tracking where arc and splashing noise was a central problem. It is beneficial for robotic welding when scanning and welding can be done simultaneously. In the case of a stub joint, it is more reasonable to scan and parameterize the entire weld groove and then generate motion paths for a welding robot. This is justified by the fact that the interface between elements in a stub joint is rather complex, which leads to the groove with variable number of weld layers and beads along the weld. In such cases, it is more reasonable to plan the entire multi-pass weld before the welding of the first bead starts. At the same time a groove has to be ground just before welding to remove rust and dust. Then the noise caused by laser reflections is a dominant noise problem, while results in As in our work, a set of groove corner points is often selected as a parametrization basis in the previously reported methods. The dominant approaches for groove parametrization are the methods based on gradients, which can be both of the first-order or the second-order, or various combination of both ,14,15. TThe parametrization methods which are the closest to the proposed procedure are the more conventional RANSAC approaches for line segment detection ,17. RANSCan be used with commercial sensors where only triangulated data points are available;Can be used with strong data noise, cause by laser reflections;Can be used for grooves in both stub and butt joints;Does not require pre-knowledge of the weld groove geometry,while the disadvantages compared to the recent works are:Might be too slow for some real-time robot path generators;Does not account for a gap between plates;Is not developed to filter out arc and splash noise.Summing up, the advantages of the proposed procedure are:Given the advantages and disadvantages above, the proposed procedure is relevant in terms of the industrial implementation as a part of the robotic welding system for large tubular joints.conventional was adopted. The algorithm used here is similar to that implemented in [This method is based on the conventional RANSAC approach for searching line segments. Therefore, a term ented in , with soComparison of experimental results from the proposed and conventional RANSAC procedures was made using an example of a V-groove, which is typical for butt joints, which means that the test object used see . The resComparison of the results for dataset 5 was made using the mean dataset 5 values only from It is noted that for the other datasets used for the comparison, we will not provide the explicit results with the maximum, minimum, and mean values, but rather give a similar summary table with mean values only. The results given in Next, the performance of the proposed and conventional RANSAC algorithms was compared using the noisy datasets 12 and 13 see , which cThe mean execution time over 10 consequent runs for the proposed method was within 0.082 to 0.095 s, while for the conventional RANSAC method, the execution time was within 1.258 to 1.858 s. The presence of data noise led to a larger variation in average point-to-segment errors. It is, however, again highlighted that both methods could be regarded as similarly precise since the errors were small in both cases.The last comparison study was performed using datasets 14 and 15, where typical N3 noise was present. The results of the comparison are given in A similar difference, as for the previous cases, in the execution times was also observed for the current study. The mean execution time for the proposed method was 0.087 s compared to 1.205–1.665 s from the conventional RANSAC method. The average point-to-segment error was of the same magnitude as in the previously studied cases. It is noted that the average errors below 0.5 mm can be considered as a good fit, which is well satisfied by both methods seeing from the results in The comparison study can be summed up with the following conclusions. Both the proposed and conventional RANSAC approaches gave similarly high precision for the noise-free and noisy datasets. The average execution time was, however, more than 10 times faster for the proposed method. The difference can be explained by the fact that the proposed method uses less iterations to find the segments, since the first point of the segment is defined. In addition, the conventional RANSAC approach uses many iterations for searching the root segment first. The root segment has relatively few points, and the algorithm does not proceed to search the other segments before the root is found, which leads to longer execution times. It is also noted that the conventional RANSAC approach needs the approximate groove geometry as an input, while the proposed method can do parametrization without any knowledge of the groove geometry.We have presented a novel weld groove parametrization procedure for typical grooves in large tubular butt and stub joints. The procedure was specifically developed to be used with industrial 2D laser scanners where raw image data might not be available, facilitating easier industrial implementation. The procedure consisted of a combination of a sequential RANSAC search and the two additional correction steps for increasing the precision of parametrization. In addition, the data noise detection steps were introduced to enable processing of noisy data, where the noise is caused by reflections between the groove surfaces. The performance of the procedure was studied experimentally using three test objects with grooves machined similarly as in the industrial applications. Two objects represented a stub joint groove, and one object represented a butt joint groove. The procedure proved to be efficient for both types of weld grooves using noise-free data. The mean execution time was within 0.061 to 0.142 s, corresponding to 170 to 400 mm/s available scanning capacity (25 mm between scans). In the cases with data noise, the parametrization results for both grooves were still of sufficient quality, while the mean execution time was within 0.046 to 0.139 s, which was similar to the noise-free cases. The performance of the proposed procedure was also compared to the conventional RANSAC approach for line segment search. The proposed method was as precise as the conventional RANSAC. However, the mean execution time was more than 10 times faster for the proposed method. Additionally, the proposed method did not require any prior knowledge of the groove geometry. The contribution of this work is a step towards robotic scanning and weld path planning for large tubular joints. Therefore, a natural topic for future work is studying the performance of the proposed procedure using a robot-fixed sensor and a full-scale tubular joint. In addition, scanning strategies facilitating the reduction in reflections and data noise should be investigated.


Impulsivity is more commonly reported in subjects with mental disorders compared to healthy subjects, suggesting a potential application of impulsivity in predicting impulsivity-related mental disorders. However, no biomarker of impulsivity available so far. This study explored the association between cerebrospinal fluid (CSF) fibroblast growth factor 21 (FGF21), a key hormonal mediator of the stress response, and impulsivity in healthy subjects.A total of 126 healthy persons subjected to surgery of anterior cruciate ligament were recruited in the present study. The impulsiveness of the subjects was evaluated by the Chinese version of the Barratt Impulsiveness Scale (BIS)-11 before surgery. CSF and blood samples of the subjects were collected before spinal anesthesia for surgery. The levels of FGF21, serotonin and dopamine in CSF and the level of FGF21 in blood of the subjects were measured by ELISA using commercial kits.Negative correlations were found between BIS-11 total score and either FGF21, serotonin or dopamine in CSF. However, BIS-11 total score was not correlated with FGF21 in blood. In addition, FGF21 was positively correlated with serotonin and dopamine in CSF, respectively. Multivariable linear regression models indicated that the decrease of FGF21 level associating with the decrease of serotonin and dopamine level in CSF contributed to the higher impulsivity. Furthermore, receiver operating characteristic curve (ROC) analysis indicated an important role of CSF FGF21 predicting high impulsivity.FGF21, serotonin and dopamine in CSF associate with impulsivity in opposite directions. The decrease of CSF FGF21 is related to higher impulsivity, and indicate that CSF FGF21 may predict impulsivity in healthy subjects. Impulsivity mainly characterized as “poorly anticipated and inappropriate hasty behaviors”, is usually relevant to negative emotions, undesirable consequences and even physical and mental health , 2. As aFibroblast growth factor 21 (FGF21) functions as a stress hormone and a strong regulator of energy metabolism . It reguIn order to find out reliable biomarkers of impulsivity, the levels of FGF21 in CSF and blood of the subjects were measured and the correlations between FGF21 and impulsivity in CSF and blood were investigated to evaluate whether FGF21 involves in regulating impulsivity. Furthermore, the correlations among FGF21, serotonin, dopamine and impulsivity were investigated to evaluate whether FGF21’s regulating effect on impulsivity associates with its regulating effects on serotonin and dopamine in CSF in the present study.A total of 126 subjects consisting of 93 males and 33 females were recruited at several Chinese hospitals in the current study. The included subjects were all scheduled to undergo surgery because of cruciate ligament injuries. CSF samples of the subjects were collected before spinal anesthesia. These subjects did not suffer from other trauma and received no medication. According to the criteria based on the Chinese version of Mini-International Neuropsychiatric Interview, subjects with mental disorders, neurological diseases, systemic diseases and central nervous system diseases were excluded from this study. Furthermore, according to the Diagnostic and Statistical Manual of Mental Disorders (4th edition), the subjects who had a diagnosis of drug abuse or dependence related to nicotine and alcohol were also excluded from the study. After approval by the Human Ethics Committee of Inner Mongolia Medical University, all participants were informed of the detail involving the right and interest in this study and then signed the written informed consent voluntarily. In addition, all methods were performed in accordance with the relevant guidelines and regulations by the Ethics approval and consent to participate. This study was performed in accordance with the Helsinki Declaration and International Ethical Guidelines for Biomedical Research Involving Human Subjects.The Barratt Impulsiveness Scale (BIS)-11 was performed to evaluate the impulsivity of each participant before the surgery. A total of 30 items made up the BIS-11 scale, and the Chinese Version was involved in three topics: (1) non-planning impulsiveness (self-control and cognitive complexity), (2) motor impulsiveness (motor impulsiveness and perseverance), and (3) attentional impulsiveness (attention and cognitive instability) . The valIn a sterile environment, a licensed anesthetist performed the lumbar puncture using a spinal needle. The needle was inserted into the L3/L4 or L4/L5 intervertebral space when a patient was in the lateral decubitus position. A 5 mL CSF sample was drawn from each patient during lumbar puncture of spinal anesthesia before surgery. A 5 mL fasting blood sample was drawn after the patient was admitted to the hospital. Every 0.5 mL fraction of a sample was collected in tubes and frozen at −80 °C immediately until analysis.The levels of FGF21, serotonin and dopamine in the CSF and the level of FGF21 in the blood were quantified by ELISA using commercial spectrophotometric measurement kits  according to the manufacturer’s protocols . All meaP value of less than 0.05 was regarded as statistically significant. All analyses were performed using SPSS 22.0 software .The continuous variable was expressed as a mean ± standard deviation, and the categorical variable was expressed as frequencies. Partial correlation analysis was performed to evaluate the association between two variables with the year and education year as the covariate. A multivariable linear regression model was performed to evaluate the effect of biomarkers on impulsivity or the association between these biomarkers in CSF. Up to now, there is no specific demarcation value to define high impulsivity, but it is very important to distinguish and screen the population with high impulsivity, so we try to use the quantile commonly used in statistics to classify the impulsivity levels. BIS total scores more than the third quartile (75%) were used to indicate a high impulsivity risk compared with others in the current study. Receiver operating characteristic (ROC) curve analysis was performed to predict the subject with high impulsivity risk. A A total of 93 males and 33 females were included in the present study, and the clinical characteristics of participants were shown in Table r =  − 0.577, p < 0.001)  , BIS motor , or BIS attention      and BIS Attention  were significantly negatively correlated with CSF serotonin   in CSF , which suggested that every 0.084 pg/ml decrease in CSF FGF21 may induce one unit increase of impulsivity. The results also showed that the decrease of CSF FGF21 contributed to the increase of impulsivity in Model 2 (adjusted for age and education years) and Model3  (Table The decrease of FGF21 contributed to the decrease of serotonin and dopamine levels in CSF in an unadjusted model (Model 1), which suggested that every 0.226 pg/ml decrease in FGF21 may induce one unit decrease of serotonin and that every 0.143 pg/ml decrease in FGF21 may induce one unit decrease of dopamine in CSF. The results also showed that the decrease of FGF21 contributed to the decrease of serotonin and dopamine in Model 2 (adjusted for age and education years) and Model 3  in CSF , every 0.034 pg/ml decrease in CSF serotonin may induce one unit increase of impulsivity, and every 0.105 pg/ml decrease in CSF dopamine may induce one unit increase of impulsivity. The results also showed that the decrease of serotonin and dopamine in CSF contributed to the increase of impulsivity in Model 2 (adjusted for age and education years) and Model 3  in CSF  was 0.79 . Our results revealed the direct relationship between CSF FGF21 and impulsivity, and the decrease of FGF21 in CSF could predict impulsivity in healthy subjects. The current study demonstrated that CSF FGF21 may be an interesting and important biomarker used to evaluate the standard of impulsivity in the general population and to screen potential population of mental disorders related to impulsivity. However, the association between CSF FGF21 and impulsivity in the patients of mental disorders with impulsivity needs to be furtherly investigated.FGF21 is considered an important pharmacological regulator and has the potential to serve as a biomarker for many diseases , 22. RecThe effect of decreased FGF21 on the increase of impulsivity may be mediated by CSF serotonin. Some early studies had evaluated the association between impulsivity and the limbic cortico-striatal systems, especially focusing on neurochemical substances such as serotonin, dopamine and noradrenaline , 25. In The effect of decreased FGF21 on the increase of impulsivity may be also mediated by CSF dopamine. FGF21 could affect dopamine signaling including changing the expression of dopamine-related genes, increasing dopamine transporter levels and directly reducing the levels of dopamine . DopaminThe monoamine oxidase (MAO) enzyme is a key enzyme of serotonin and dopamine metabolisms. It has been reported that the MAO enzyme was closely associated with impulsivity, especially for low MAO B activity . ChronicAlthough the questionnaire measured impulsivity remains controversial, the BIS-11 scale is the most suitable method available now to assay the impulsivity of subjects . Since wIn summary, FGF21, serotonin and dopamine in CSF associate with impulsivity in opposite directions, and the effect of CSF FGF21 on impulsivity may be related to the regulating effects of FGF21 on serotonin and dopamine in CSF. In addition, the present study demonstrated that CSF FGF21 may be a biomarker of impulsivity in the currently healthy subjects.


Background: In most cases, palliative care is prescribed to adults diagnosed with cancer. The definition of the most suitable therapy for an effective sedation in terminal cancer patients still represents one of the most challenging goals in medical practice. Due to their poor health, the correct dosing of drugs used for deep palliative sedation in terminal cancer patients, often already on polypharmacological therapy, can be extremely complicated, also considering possible drug-to-drug interactions that could lead to an increased risk of overdose and/or incongruous administration with fatal outcomes. The case of a terminal cancer patient is presented, focusing on the “adequacy” of administered therapy. Materials and Methods: A young male, affected by Ewing sarcoma, attending a palliative care at his own home, died soon after midazolam administration. Toxicological and histological analyses were performed on body fluids and organ fragments. Results and Discussion: Morphological reliefs evidenced a neoplastic mass, composed of lobulated tissue with a lardy, pinkish-gray consistency, extending from the pleural surface to the lung parenchyma, also present at the sacrum region (S1–S5), at the anterior mediastinum level, occupying the entire left pleural cavity, and infiltrating the ipsilateral lung. Metastatic lesions diffused to rachis and lumbar structures. The brain presented edema and congestion. Toxicological analyses evidenced blood midazolam concentrations in the range of 0.931–1.690 µg/mL, while morphine was between 0.266 and 0.909 µg/mL. Death was attributed to cardiorespiratory depression because of a synergic action between morphine and midazolam. The pharmacological interaction between midazolam and morphine is discussed considering the clinical situation of the patient. The opportunity to proceed with midazolam administration is discussed starting from guidelines recommendation. Finally, professional liability outlines are highlighted. Pain has always been a source of concern for mankind and the subject of a ubiquitous commitment to understand and control it. Remedying suffering and offering relief to the patient mean improving their quality of life and, in general, the quality of the health care provided. When the patient’s health conditions worsen and curation is no longer possible, palliative care becomes the only feasible approach, the purpose of which changes as the patient’s health conditions change . If the In March 2010, a legislative decree was issued in Italy focusing on palliative care and pain therapy, also introducing the at-home sedation . The ItaTerminal cancer patients are among the most fragile and critical and the definition of the most suitable palliative care is still an open challenge: the precarious health conditions that these patients generally present in the terminal stages of their lives, together with therapies (often polytherapy) already prescribed, contribute to complicate the choice of the best approach to ensure adequate quality of life. If sedation must be ensured for a short time period, blood pressure, oxygen saturation, and respiratory rate have to be monitored, as well as the degree of sedation established according to the RAMSEY scale; therapy needs the presence of sanitary personnel during the first 10–15 min.Finally, palliative care therapy itself can involve the use of several active principles, for which the clinician must carefully evaluate the possible drug-to-drug interactions considering the specific patient’s health conditions.Opiates, mostly morphine, in combination with midazolam and haloperidol, are widely used for symptom control . Drug-toWithin this item, the present paper presents the case of a terminal cancer patient who died at their own home in strict temporal relation with a midazolam administration. Toxicological data are discussed in view of guidelines and recommendations for a safe management of terminal cancer patients and possible professional liability.A young Italian male was diagnosed with Ewing’s sarcoma in the sacral region when he was 24 years old. Despite second- and third-line chemotherapy treatments, as well as radiotherapy, a chest recurrence of sarcoma presented after four years, with costal, pleural, pulmonary, and cardiac involvement. Due to his worsening health conditions and the severity of the painful symptoms, the young man began a treatment of palliative care in an Onco-Hematology Department, including morphine (0.8 mL/min) for analgesia. As the disease worsened, he decided to continue with palliative care at his home and was entrusted to the Territorial Service for Integrated Home Care. The following therapy was prescribed: oxygen, 3 L/min; paracetamol, 1 g iv, at occurrence; morphine, 100 mg at 1.5 mL/h, with continuous infusion; morphine, 3 mg/3 mL infusion in physiological solution, at occurrence; no other drugs were prescribed for patient sedation. The young man died after three days from the arrival at home. Although the clinical diary did not report any worsening of the condition of the young man that justified the implementation of analgesia, empty bottles of midazolam were found in the bedroom. A total of eight empty ampoules (six of 5 mg and two of 15 mg) were found in the bedroom, thus suggesting a possible 60 mg midazolam administration. The parents reported that the physician proceeded with the administration of midazolam , moving away immediately after. The parents called the emergency medical services, who reported the death to the Prosecutor Office (P.O.). Both autopsy and toxicological analyses were performed, in an attempt to elucidate the exact cause of death , as well as to verify eventual professional liabilities.N,O-bis (trimethylsilyl) trifluoroacetamide (BSTFA) derivatizing agent from Acros , and HPLC-grade solvents from Carlo Erba .Certified standard solutions of drugs of abuse used for confirmation analysis in gas chromatography/mass spectrometry (GC/MS) were from Cerilliant-Merck , Enzyme-Linked ImmunoSorbent Assay (ELISA) screening tests were performed on a Dynex-DSX system from Technogenetics , using forensic blood kits from Abbott for AMP/MAMP/MDMA, barbiturates, benzodiazepines, buprenorphine, cannabinoids, cocaine, fentanyl, ketamine, methadone, opiates, oxycodone, tricyclic antidepressants, and zolpidem.®-5MS (30 m × 0.25 mm × 0.25 µm) capillary column . Data were processed using the Xcalibur software (version 4.0.27.13) from ThermoFisher.GC/MS analyses were performed using an ISQ single-quadrupole mass spectrometer directly linked to a Trace1300 gas chromatograph equipped with a split-splitless autosampler Al1310, all from ThermoFisher . Gas chromatographic separations were performed with a RxiHeadspace gas chromatographic/mass spectrometric (HS-GC/MS) analyses were performed on an HP6890 series gas chromatographer provided with a HP7694E autosampler and a 5973 single-quadrupole mass spectrometer ; chromatographic separation was accomplished by a CP PorabondQ capillary column , and data were analyzed using the MSD Chemstation software (D.02.0.275 version) from Agilent Technologies .full scan and selected-ion monitoring mode (GC/MS-SIM). The eventual presence of ethyl alcohol or any other volatile chemicals was also verified, by analyzing portal vein blood by HS-GC/MS.Biological fluids  and organ homogenates (from brain and liver) were used for toxicological analyses; femoral blood, usually used for post-mortem toxicological analyses , was notToxicological analyses were also performed on liquid residues recovered from the central venous catheter present in the under-right clavicular region of the deceased; solutions of three infusion lines see , part B The autopsy highlighted the presence of a central venous catheter placed in the right clavicular vein, connected distally with three different infusion lines  to 1.7 µg/mL (aorta vein blood); the benzodiazepine was also detected in brain homogenate (1.3 µg/g), while bile, urine, and liver resulted as negative. All analyzed biological matrices resulted as positive to morphine, with concentrations from 0.3 µg/mL (aorta vein blood) up to >0.8 µg/mL ; the brain and liver presented morphine concentrations of 0.9 ng/g and >0.8 µg/g, respectively.Results on morphine are in line with pharmacological therapy prescribed to the patient. He presented intense painful symptoms, as the neoplasm infiltrated a large part of the pelvis skeleton, the last lumbar vertebral metamers, numerous costal elements of the left hemithorax in one on the entire pleural surface, and almost all the ipsilateral lung. The prescribed analgesic therapy provided for continuous morphine infusion (and paracetamol at occurrence), justified by a picture of certainly very intense pain, well documented in the medical record.Different considerations can be made with respect to midazolam concentrations. Regarding the quantitative levels of the drug determined in the different biological matrices, it must be underlined as post-mortem data cannot be simply interpreted by comparison with in vivo therapeutic concentrations. Modifications occurring immediately after death  account for significative variations between ante- and post-mortem drug levels ,17. CommToxicological analyses performed on solution residues recovered from the central venous catheter evidenced the presence of midazolam in Part A-yellow line and Part B solutions.Despite being provided in palliative sedation protocols, simultaneous administration of a sedative-hypnotic benzodiazepine in a terminal cancer patient already under continuous morphine infusion must be carefully evaluated. When administered to healthy patients, sedative-hypnotics induce effects on respiration comparable to those recorded during natural sleep even at hypnotic doses . Convers“depending on the size of the dose, the particular pharmacologic response, and the patient’s sensitivity” [Midazolam is classified as a “short-acting” drug, with a rapid onset of the pharmacological effects , furtheritivity” .Toxicological findings showed the presence of midazolam in part A (yellow line) and part B solutions recovered from the central venous catheter present on the body, confirming the hypothesis of benzodiazepine administration through such a device. In view of its position on the body (under-right clavicular vein), the positivity found in all blood samples attests the effective midazolam distribution. In this regard, particularly relevant is the positivity of the blood sample from the portal vein: if the midazolam did not have time to distribute, such a sample would have been substantially negative. Moreover, considering the positivity of the brain homogenate sample, the drug had the opportunity to exert its pharmacological effects before the patient’s death. Negative results obtained for bile, liver, and urine toward midazolam strongly supported the hypothesis of a strict correlation between drug administration and death. Such an aspect is of great relevance to assess the sanitary management, as discussed below.essential palliative care drug [to the relief of symptoms and the distress it causes [In the case presented here, the midazolam administered dose, estimated by the empty ampoules (six of 5 mg and two of 15 mg) found in the deceased’s bedroom, was about 60 mg by multiple intravenous injections performed in a short time sequence, therefore comparable to a single injection. Such an administered dose results as higher than dosages reported in the literature for palliative sedation of terminal cancer patients. In their revision of the literature, De Graeff and Dean reported the use of different drugs (both in terms of active principle and dosage) among countries, but, generally, midazolam is the sedative of choice, due to its several advantages, such as short half-life, few side effects, anxiolytic, antiepileptic, and muscle relaxant properties, apart from sedative effects . The admare drug : literatare drug , 23–58)are drug , and up are drug . As evid–58are drt causes . Such ant causes . In factt causes . In the Pharmacological management of palliative sedation must be carried out with particular care, as it is always recommended to: (i) draw up an adequate clinical diary to report the therapeutic responses and possible side-effects progressively evaluated; (ii) gradually increase the drug’s dosages up to the desired sedation level; (iii) weigh the degree of sedation and any relative changes to therapy ,31. In g


Pediatric fecal matter transplant (FMT) clinical trials relying on “healthy” donor stool use screened adult donor stool, likely assuming safety and efficacy. However, we consider how adult donor stool could instead be posing risks of atypical development or transmission of early disease, which could be prevented with age-matching donors and recipients for FMT.The gut microbiome has been identified as a potential therapeutic target to combat pediatric intestinal and extraintestinal diseases through FMT. FMT involves the transfer of “nondiseased” stool into the gastrointestinal (GI) tract of an individual with the disease in attempts to replenish the gut microbiota and ameliorate adverse GI symptoms. Currently, no standard methodology exists for clinical trials investigating FMT efficacy. Key elements such as donor selection processes are often based on drastically different criteria but usually involve adult stool donors even in pediatric FMT clinical trials. We consider how the usage of adult donors may be of concern when considering the long-term implications of FMT on pediatric health. The pediatric microbiome plays an important role in immune, GI, and neurological development and to introduce adult donor stool to an already dysbiotic microbiome could lead to atypical maturation. Furthermore, selection of nondiseased stool is based on current screening protocols. Screened and deemed “nondiseased” adult donor microbiota could be showing early disease markers for diseases that are not yet visible with current donor screening protocols, putting pediatric recipients at risk for disease development. Current pediatric guidelines have yet to consider these specific pediatric risks, which could be jeopardizing the long-term health and development of pediatric patients and influencing the future of pediatric therapeutics.The microbiota is largely shaped in early childhood. Antibiotic usage in early childhood has shown to increase the risk of acquiring conditions such as inflammatory bowel disease (IBD), asthma, allergy, and eczema , 2. ThisThroughout childhood, adolescence, and adulthood, age is associated with drastic differences in composition and functional gene potential of the microbiome . Age greIn a pediatric FMT clinical trial, considerations for donor stool should include both microbial factors, such as similarity of microbial species between donor and recipient, as well as factors for host intestinal tolerance toward the donor microbes. Because the gut microbiota of young children, adolescents, and adults are all distinct, the necessary microbiota across development is crucial for typical neurological, immunological, and GI development –4, 6. IfClostridioides difficile infection (rCDI) (NCT02134392). In these pediatric trials, the age of the stool donor is listed as either an adult or is not mentioned in study record details.In the pediatric population, active FMT clinical trials include treatment of intestinal colonization of extended-spectrum resistant Enterobacteriaceae (NCT02543866), IBD (NCT03399188), autism spectrum disorder (NCT03426826), ulcerative colitis (NCT03582969), Crohn's disease (NCT03378167), and refractory Methodology within FMT clinical trials vary with donor selection procedures being a particular area of heterogeneity . Fecal dScreening efforts are established to not only ensure stool viability but robustly reduce the chance of transmitting infection or active medical comorbidities from donor to recipient . ScreeniDonor selection methodology is a particularly large area of ambiguity. For example, a systematic review of FMT clinical trials reported before 2017 determined that out of 85 FMT clinical trials, almost 50% of published studies did not report donor selection eligibility criteria in their publications . This reTrial method heterogeneity and uncertainty surrounding true efficacy further exacerbates the concerns for safety in FMT clinical trials. Safe stool is as safe as how it has been screened, and screening can only include testable pathogens already established to directly cause disease. However, the definition of what can cause disease is constantly evolving. For example, FMT has revealed the possibility of transmission of diseases previously assumed as nontransmissible. A patient developed issues with significant weight gain following an FMT from a healthy, but overweight, donor leading to FMT guidelines to suggest screening for donor body mass index . This poCurrent pediatric guidelines suggest donor selection should involve adults aged 18 and older based on medicolegal considerations . While aEarly life disruptions to the microbiota can already increase an individual's susceptibility to a variety of immune, metabolic, neurological, and psychiatric diseases . This phEarly disease markers for a variety of gut microbiome associated diseases have not yet been identified. These early disease markers could be characteristic changes occurring in the gut of an adult donor, years before diagnosis of disease, and invisible with current stool-screening guidelines. It is established that bidirectional communication between the brain and GI tract has been implicated in a variety of neurological diseases. Transmission of early disease markers from a variety of diseases could occur; here, we will illustrate the issue using Parkinson's disease (PD) as an example. PD has characteristic changes in the GI tract including constipation and gut dysbiosis with increased inflammation and reduced short-chain fatty acid production. Adults with REM-sleep behavior disorder, a prodromal stage of PD, already have the same pattern of dysbiosis . ConstipTo contextualize early disease marker transmission using specific evidence from pediatric FMT, a study of the gut microbiome of pediatric recipients following FMT with “healthy” adult donor stool showed the potential for acquisition and persistence of antimicrobial genes from the donor . AlthougWe are concerned that adult donors beginning to generate characteristic microbiome profiles of adult-onset disease could be acting as FMT donors for pediatric FMT trials, potentially generating long-term implications for the recipient child with their GI tract being introduced to characteristic pathogenic changes in childhood. Matching pediatric FMT recipients with pediatric donors could largely reduce the possibility of adult-onset neurodegenerative disease marker transmission and allow for less interruption of age-specific maturation of the gut microbiota.With past efforts focused on the promotion of immediate safety for pediatric FMT recipients, the field is ready for conversations surrounding long-term safety and healthy development in pediatric FMT recipients. Optimal donor selection should be a focus of these conversations, with considerations of matching donors and recipients by age being prioritized. Age-matching could reduce the exacerbation of the child's atypical immune, GI, metabolic, and neurological development to allow for parallel interplay of microbiota development with typical physiological development.The idea of age-matching is not without an introduction of its own novel risks, such as possible transmission of childhood-onset diseases including asthma or allergy to pediatric recipients. However, we argue this phenomenon could still occur with the introduction of adult donor microbiota because it could be affecting typical immunological development. Furthermore, screening for risk factors for allergy and asthma, such as antibiotic usage, mode of delivery, and formula feeding in pediatric donors, could aid to protect against this occurrence.A joint-position paper from the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition similarly argues that further research into age-matching is warranted due to concerns of long-term efficacy and safety with adult donors . Age-matCurrently pediatric FMTs are changing children's lives, treating persistent, and sometimes otherwise incurable, diseases, demonstrating the power of the approach. FMT trials explore increasingly diverse applications for pediatric intestinal and extraintestinal diseases and long-term clinical considerations for health and development will be increasingly important. Given the increasingly recognized role of the gut microbiome in adult diseases including neurodegenerative disorders, we believe choosing age-matched donors for pediatric FMTs will likely be the best safe-guard to reduce potential future complications.At time of submission all clinical trials statuses mentioned in the manuscript are listed as: NCT02543866 (recruiting), NCT03399188 (recruiting), NCT03426826 (recruiting), NCT03582969 (recruiting), NCT03378167 (recruiting), and NCT02134392 (recruiting).https://clinicaltrials.gov/.Current trial statuses can be accessed at AM conceived the opinion and drafted manuscript. BF and SA-C contributed expertise to review and critique final manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.