A 72-year-old man, who was treated 10 years earlier with endovascular aortic aneurysm repair, presented with a fever. Considering the concern of stent graft infection, the patient was treated with antibiotics, but his condition did not improve. He underwent stent graft resection and reconstruction with a Dacron graft. Pathological analysis of the aortic wall and computed tomography revealed recurrent intimal sarcoma, and the patient underwent resurgery. During follow-up, he underwent two additional resections for local recurrence, but he died 17 months later. Our results suggest that intimal sarcoma should be considered during the follow-up after endovascular aortic aneurysm repair. Owing to early blood metastasis and resistance to chemotherapy, patients with intimal sarcoma have a poor prognosis. In this report, we describe our experience with intimal sarcoma following endovascular aortic aneurysm repair (EVAR). This case report has been approved by the institutional committee on the ethics review board (registration number: 5504).Intimal sarcoma of the abdominal aorta is rare. Intimal sarcoma presents with intraluminal growth with obstruction of the lumen of the vessel of origin and seeding of emboli, and it is difficult to diagnose and is often diagnosed in surgical specimens or at autopsy.3). Multiple sets of blood cultures were negative for bacteremia. Echocardiography showed a normal left ventricular ejection fraction and no valvular vegetation. Compared with the computed tomography (CT) scan from the previous hospitalization, enlargement of the aneurysm sac, periaortic thickening, and periaortic inflammation related to infection were noted in the present CT scan , which was placed at another institution 10 years before the visit to our clinic. He was admitted to the hospital of origin complaining of fever and physical weariness, which had persisted for four months previously. Symptoms did not improve after antibiotic treatment, and the patient was referred to our department. Laboratory tests at admission revealed an elevated C-reactive protein (10.6 mg/dL) and no leukocytosis (white blood cell count of 7480/mmIntimal sarcoma is a rare malignant neoplasm that arises in the aorta, and its defining features are intraluminal growth with obstruction of the lumen of the vessel of origin and seeding of emboli to peripheral organs. A PubMed literature search using the search terms EVAR and sarcoma revealed only 12 cases of primary abdominal aortic sarcoma after EVAR ( The age of onset of aortic sarcoma after EVAR ranges from 56 to 85 years. Aortic sarcoma is defined as an intraluminal growth that obstructs the lumen of the vessel and emboli to the peripheral organs. However, the patients do not present with symptoms of embolism after EVAR, as in the present case. This investigation suggests that EVAR suppresses tumor growth in the aortic lumen and prevents embolism. However, most cases of aortic sarcoma after EVAR reported in the literature have described an association with foreign materials, such as Dacron or nickel and titanium alloys in SGs. In a study of 35 cases of angiosarcomas by Fenton et al., 23 cases were associated with the use of these prostheses. Therefore, the physical characteristics of the implanted materials are considered essential factors for tumorigenesis. The duration from EVAR to tumorigenesis was 4–10 years, which also suggests an association with these prostheses.Most patients with aortic intimal sarcoma are middle-aged, and the prognosis of intimal sarcomas is generally poor. The CT findings of infected aneurysms include disruption of intimal calcification; irregular arterial lumen; and periaortic gas, fluid, and/or hematoma. However, CT findings of infected aneurysms with overlapping characteristics of intimal sarcoma are more common. Half of the case reports retrieved in this report were diagnosed with graft infection. The ultrasonographic findings of intimal sarcoma were reported by Kamran et al. to have a small mass-like component of intermediate echogenicity, which shows internal vascularity in the color Doppler image. Conversely, the ultrasonographic findings of infected aneurysms are not characteristic, but the shape of the aneurysm is irregular, and the presence of air is noted. We have not confirmed any ultrasonographic findings in our case. PET scans show avid fluorodeoxyglucose uptake, but PET scans are not performed unless a tumor is suspected. It is important to be cautious of neoplastic lesions during follow-up after EVAR. However, imaging seldom permits the preoperative diagnosis of aortic sarcoma, and graft infection is often presumed, as in our case. In previous studies, preoperative diagnosis suspected graft infection in 6 of 11 cases, and in 7 cases, the diagnosis of aortic sarcoma was made by immunohistochemical examination of the surgical specimens. In our case, the final histopathological examination led to a diagnosis of intimal sarcoma. The treatment of intimal sarcomas remains difficult. Currently, in the absence of metastases, surgical resection of the tumor is the first-line treatment for intimal sarcoma. The role of adjuvant chemotherapy and radiotherapy remains unclear. However, most patients with aortic sarcoma have metastasis at the time of diagnosis, due to which the five-year survival rate remains poor.CT is a useful diagnostic tool for angiosarcomas. The imaging characteristics of aortic sarcoma include protrusive vegetation or nodular soft-tissue components, lack of atherosclerosis in the area of suspicion, heterogeneous thrombus, evidence of enhancement and neovascularity, and persistent enlargement of the excluded sac. However, there is a case report in which patients underwent en bloc resection of the aorta and common iliac vessels and survived for eight years from diagnosis to death. Early diagnosis is important because complete resection of the primary lesion suggests the possibility of long-term survival. In this case, the patient was misdiagnosed with SG infection and underwent four months of antibiotic therapy, but the tumor expanded. During follow-up after EVAR, attention should be paid to neoplastic lesions, aneurysm sac enlargement, and graft infections.In a study published by Thalheimer et al., the median survival time was only 12.8 months after diagnosis, and metastases were present in 76.2% of cases.We presented a rare case of intimal sarcoma mimicking an infected EVAR. Intimal sarcomas after EVAR are rare and difficult to diagnose. Attention should be paid to neoplastic lesions, aneurysm sac enlargement, and graft infections during follow-up.


Craseonycteris thonglongyai) and a 150-ton blue whale . Such diversity allowed mammals to colonize all continents and a great variety of habitats, from alpine zones to mesopelagic oceans, from hyper-arid deserts to hyper-humid tropical forests. Nonetheless, human impacts such as poaching, fragmentation of habitats, climate change, pollution, and introduction of exotic species, among others, have negative consequences on mammalian populations  comprise a highly diverse vertebrate group, amounting to 6,495 living species recognized to date . The impulations . Of the ulations . In otheCurrently, a major threat to mammals is the contraction of habitats, which poses a decrease in the species’ range and abundance, which also reflected in the genetics of organisms. Genetics applied to mammal conservation is anchored in the principles of population genetics, linking population size to susceptibility to stochastic events. In large populations reduced to small sizes, genetic diversity tends to be rapidly lost, increasing the possibility of inbreeding, and the fixation of deleterious variants, which may reduce the individual fitness. Thus, unrevealing the amount of genetic diversity in wild populations and how it is structured along the geographical distribution of the species are key contributions to developing conservation strategies for mammals . These cAbrothrix hirta using 119,226 transcriptome-derived SNP loci and found four highly well-supported lineages, which were suggested to be considered as ESUs and to be recognized at the subspecific level. Phylogeographic approaches are very useful for the detection of interspecific divergences, especially in regions that experienced marked past climatic fluctuations. Reding et al. examined the phylogeographic structure of the gray fox Urocyon cinereoargenteus in the United States, instigated by previous data which revealed a deep divergence between populations from western and eastern parts of the country. The phylogenetic analysis of the control region and complete mitochondrial genome corroborated the east/west phylogeographic break, revealing a secondary contact zone at the Great Plain Suture Zone. In addition, the authors found Urocyon littoralis, currently considered a distinct species, nested within U. cinereoargenteus western clade. Although the impact of habitat contraction and fragmentation is expected to be more intense in large mammals, in particular in species that present highly specialized behavior, Barragán-Ruiz et al. provide original data on the distribution of genetic variation (based on microsatellites) in the giant anteater Myrmecophaga tridactyla along a human-modified landscape, evidencing low genetic structure. However, the authors detected moderate levels of genetic diversity, recent bottleneck and inbreeding signatures, and a past demographic reduction, which was suggested to potentially impact this emblematic species. Similarly, Chaves et al. accessed the genetic diversity among populations of the Galapagos fur seal Arctocephalus galapagoensis, considered Endangered by the IUCN, along with breeding rockeries located on four islands of the Galapagos. The authors found a structure composed of at least two clusters, and indicative of gene flow between two islands, suggesting that migrations are driven by the local differences in marine productivity. Chaves et al. also detected significant heterozygosity excess in microsatellite markers in three populations, which indicates the occurrence of past bottleneck events. The manuscript of Caballero et al. analyzed the mitochondrial DNA sequencing of two manatee species (Trichechus manatus and T. inunguis) in Colombia, in locations never studied before. The results showed previously unknown genetic diversity for T. manatus and significant population differentiation probably caused by human interventions in one of the rivers sampled. The authors also demonstrated that environmental DNA analysis can be used to monitor the presence and persistence of manatees in the environment by detecting the DNA traces of these species in the water of rivers.The investigation of intraspecific genetic diversity is crucial for the detection of lineages characterized by unique evolutionary histories. Valdez and D’Elía analyzed the geographic distribution of the genetic diversity of the sigmodontine cricetid Carnovale et al. addressed the recent evolutionary history of populations of the caviomorph rodent Ctenomys in the Argentinean Pampas, using mitochondrial DNA sequences, and revealed that C. talarum and C. pundti complex might be considered as the same biological species, or represent lineages going through an incipient differentiation process. Such systematic updates can be actively used in the conservation strategies for these organisms, considered vulnerable and endangered, respectively. DNA sequencing has allowed conservationists to assess previously unknown genetic information of endangered species that is essential to take actions in conservation programs, e.g., to decide locations where species should be released back into the wild. Taxonomic uncertainties represent difficulties for effective conservation action in target species. The red brocket deer Mazama americana has been demonstrated to comprise a polyphyletic complex of cryptic species characterized by a marked chromosomal divergence. Aiming to solve part of such a problem, Peres et al. collected a specimen in the vicinity of the region linked to the binomial Mazama rufa (so far a synonym of M. americana) and designed a neotype. Following, the authors tested the specific validity of M. rufa through an integrative analysis using molecular , chromosomal and morphological databases. The results revealed that M. rufa is supported as a species distinct from M. americana sensu stricto, and it composes a sister clade of “M. americana” from East Amazon. The authors also analyzed fecal DNA and used the results obtained to perform modeling of the species potential distribution. Mazama rufa is potentially distributed from the southern Amazon to eastern Argentina.A key field for the conservation genetics of mammals is systematics. Reevaluation of phylogenetic relationships in the speciose genera is fundamental to constructing conservation strategies, in particular when species are vulnerable or threatened. Canis lupus) is a top predator species whose persistence and interactions have important effects on ecological aspects of other species’ lives and their surrounding environment. The author reviewed genetic studies using different molecular and bioinformatic tools as a source of information for the identification of wolf-dog hybrids in Europe, the introgression patterns observed, and to estimate potential causes and consequences of hybridizations. The author also discussed the importance of implementing standardized and reliable methods to identify wolf-dog hybrids before making decisions for conservation actions and population management.Hybridization and introgression were not usually listed among the major extinction threats until recently. If the process of hybridization occurs naturally, it is considered part of the evolutionary history of the species involved. However, this phenomenon deserves special attention when arising as a consequence of human actions , as it cWhat draws attention in most of the manuscripts on this topic is the survey of microsatellites and mitochondrial DNA sequences, indicating that they remain important and cost-effective markers for the analysis of genetic diversity, inbreeding status, kinship, and genetic structure in mammals, particularly in species that inhabit South America. However, genomic data will empower the delimitation of cryptic species and ESUs, redrawing the studies on populations of endangered mammal species.


The nuclear reactor pressure vessel is an important component of a nuclear power plant. It has been used in harsh environments such as high temperature, high pressure, neutron irradiation, thermal aging, corrosion and fatigue for a long time, which puts forward higher standards for the performance requirements for nuclear pressure vessel steel. Based on the characteristics of large size and wall thickness of the nuclear pressure vessel, combined with its performance requirements, this work studies the problems of forging technology, mechanical properties, irradiation damage, corrosion failure, thermal aging behavior and fatigue properties, and summarizes the research progress of nuclear pressure vessel materials. The influencing factors of microstructures evolution and mechanism of mechanical properties change of nuclear pressure vessel steel are analyzed in this work. The mechanical properties before and after irradiation are compared, and the influence mechanisms of irradiation hardening and embrittlement are also summarized. Although the stainless steel will be surfacing on the inner wall of nuclear pressure vessel to prevent corrosion, long-term operation may cause aging or deterioration of stainless steel, resulting in corrosion caused by the contact between the primary circuit water environment and the nuclear pressure vessel steel. Therefore, the corrosion behavior of nuclear pressure vessels materials is also summarized in detail. Meanwhile, the evolution mechanism of the microstructure of nuclear pressure vessel materials under thermal aging conditions is analyzed, and the mechanisms affecting the mechanical properties are also described. In addition, the influence mechanisms of internal and external factors on the fatigue properties, fatigue crack initiation and fatigue crack propagation of nuclear pressure vessel steel are analyzed in detail from different perspectives. Finally, the development direction and further research contents of nuclear pressure vessel materials are prospected in order to improve the service life and ensure safe service in harsh environment. In recent years, the global energy crisis has swept the world. Fossil energy, such as coal, oil and natural gas, is being consumed at a visible rate, resulting in energy shortages. Currently, the world is dominated by coal power generation. However, the coal power generation not only causes environmental pollution but also leads to energy exhaustion, which will cause the global power shortage and price rise ,2. NucleNuclear reactor pressure vessel (RPV) is an important component of nuclear power plant and cannot be replaced during the entire life cycle. Therefore, the steel used for RPV was generally improved on the basis of the previous generation of RPV materials. The initial material of RPV was C–Mn steel used for the boiler. The plate of SA212B, and the forgings of SA105 and SA182, were selected as the steels for first-generation RPV due to their good welding performance and high strength. However, the impact toughness and high temperature performance of C–Mn steel are poor, and the hardenability was insufficient, so the first generation of nuclear pressure vessel steel has been replaced.The first generation RPV material was replaced by Mn–Mo-series low-alloy high-strength steel SA302B plate in order to improve the strength and toughness, which was called the second generation of RPV steel. Subsequently, the modified SA533B was made by adding 0.4–1% Ni element on the basis of SA302B, which had good strength, hardness and toughness, so it was widely used in nuclear reactor pressure vessels .The possibility of reheat cracks in SA508Gr.2 steel was reduced by decreasing the contents of C, Cr and Mo. Meanwhile, the Mn was added to improve the strength of RPV materials. Therefore, SA508Gr steel was improved as the third-generation nuclear reactor pressure vessel material under this background . At presWith the improvement of safety performance and increase of service life of nuclear power plants, RPV materials are developing towards the direction of “large-scale integrated design” and “high safety and longevity operation”, which requires the steel used in RPV to have better hardenability and higher strength and toughness ,17,18. WThe safety of nuclear power plant depends on the reliability of nuclear island equipment, especially the nuclear vessel equipment that directly or indirectly contact with radioactive media, such as nuclear reactor pressure vessels, steam generators, pressurizers, etc., and the RPV also plays a role in maintaining the operating pressure balance in the reactor. RPV materials were constantly exposed to high temperature and high pressure during the service. They determined the safety and service life of nuclear power plant to a great extent ,28,29,30In addition, the RPV nozzle was also connected with the primary circuit main pipeline cooling system. The RPV materials were not resistant to corrosion, so a layer of austenitic stainless steel or nickel-based alloy corrosion-resistant lining would be overlaid on its inner wall to prevent corrosion. The primary cooling system was isolated from the outside world and oxygen concentration was very low, which would not cause corrosion damage to the nuclear pressure vessel system during the normal service conditions. However, the damage to the corrosion-resistant surfacing layer, stress corrosion cracking of alloy pipe penetrations at the bottom and upper closure of nuclear pressure vessels and potential leakage sources  would lead to corrosion behavior and decrease the service life of materials during the long-term service of RPV. Therefore, corrosion was also one of the service environments of the RPV.The service life of nuclear power plants had been increased from the original design of 40 years to 60 years with the rapid development of nuclear power technology, and it would be extended to 80 years in the future ,33,34. TRPV materials were subjected to different stages before application, such as smelting, ingot casting, forging, preheat-treatment, rough machining, quenching and tempering heat treatment, post-weld heat treatment, and delivery. Once the forging parameters were not well controlled during the forging, it was easy to cause mixed-crystal microstructures and other defects in the RPV materials, which would seriously influence the safe service performance ,17,43. T−1. The dynamic recrystallization process and abnormal grain growth process were shown in −1.Dai et al.  studied The materials would be in a high temperature state after hot deformation, which would lead to the materials to undergo static recovery, static recrystallization and grain growth behaviors. Qiao et al.  studied The ASTM standard  specifie2C carbides. The increase of Cr element had no effect on the ultimate tensile strength of SA508Gr.4N steel, but the toughness could be improved by refinement the size of carbides. The change of alloying element content is directly reflected in the change of mechanical properties, but the essential factor is the change of microstructure. For example, carbon content increases the strength of nuclear pressure vessel materials, Ni can improve the hardenability of nuclear pressure vessel materials, and Cr element can refine carbides size. Kim et al.  found thHeat treatment process can change the microstructure of materials, such as refining carbides, increasing high-angle grain boundaries (HAGBs), and then change the mechanical properties of materials. Ahn et al.  added thThe RPV materials have the characteristic of large size and large wall thickness, which will cause the wall thickness effect during the quenching and tempering heat treatment. As a result, the cooling rate gradually decreased along the surface of the nuclear pressure vessel material toward the center. Martensite structure was easy to form on the surface due to the high cooling rate, mixed structure of martensite and bainite was easy to form in the transition layer, and bainite or ferrite structure was easy to form in the center due to the low cooling rate. On the other hand, the larger the cooling rate, the smaller the grain size and martensite block size of the material, which would lead to the materials with more volume fraction of HAGBs, and then improved the mechanical properties.Yang et al.  obtainedF) matrix. The M/A islands would decompose and be divided into five stages during the tempering: Firstly, the M/A islands decomposed into carbides and bainite ferrite matrix; Secondly, the carbides spheroidize and growth with the increase of tempering time; Thirdly, the phenomenon of merging of the lath boundaries would be occurring; Fourthly, carbides growth at grain boundaries; Finally, the new M/A islands were formed when the tempering temperature exceeded the AC1. The carbon content in M/A islands was much higher than that in BF matrix, and M/A islands belong to strengthening phase compared with the BF matrix. The tensile strength of the nuclear pressure vessel material decreased, and the toughness increased with the strengthening phase decomposed into the fine carbides and bainite ferrite matrix. However, the impact toughness of the material decreased when the fine carbides were coarsened. In addition, Xie et al. [The core structure of nuclear pressure vessels steel is generally granular bainite due to the large wall thickness of nuclear pressure vessels. Dai et al.  and Li ee et al.  added loThe size of carbides had a significant effect on the impact toughness of SA508Gr.3 steel, Lee et al.  found thWhere the nuclear pressure vessel material was connected to the primary high-temperature water environment. The high-temperature water would decompose H during the operation of the nuclear power plant, which might lead to the RPV materials to absorb H and thus affect its mechanical properties. Liu et al. ,62 invesWu et al.  studied The above research results showed that the increase of Ni and Mo content could improve the hardenability of the materials, which was beneficial to obtain martensite microstructure of nuclear pressure vessel steel. In addition, the increase of Ni content could also refine the grain size and martensite block, which would lead to higher HAGBs. The increase of Mo and Cr content could refine the carbides and made it uniformly distributed on the matrix. HAGBs and fine carbides could effectively prevent crack propagation and improve the mechanical properties of materials.Heat treatment parameters included cooling rate, heating temperature and holding time. The cooling rate of the heat treatment gradually decreased from the surface to the center with the increase of the wall thickness of the RPV materials, the grain size and the martensite block size increased, the volume fraction of the HAGBs decreased, and the mechanical properties of the materials deteriorated. In addition, the granular bainite would decompose into ferrite and fine carbides during the quenching and tempering heat treatment, which would decrease the tensile strength of the material, but was beneficial to improve its impact toughness.There was no consistent conclusion on the influence of H content on the tensile strength of nuclear pressure vessel materials, but it could be determined that the increase of H content in materials would significantly deteriorate the impact toughness, and the fracture type would change from ductile fracture to brittle fracture. This was mainly attributed to the fact that the carbides could capture H and form Cottrell atmosphere around it, which would cause the reduction of the bonding force between carbides and matrix, and then formed cracks.The irradiation damage process of materials can be defined as the process that the incident particles transfer energy to the target, which leads to the redistribution of target atoms in the target. DPA (displacements per atom) is the number of times the atoms in a material leave the equilibrium position, and it is the basic unit of irradiation damage of a material ,66,67. T2+ at 290 °C, and found that the hardness of SA508Gr.4N steel increased with the increase of irradiation doses . Shimodaira et al. [To investigate the effect of irradiation on hardness, Bai et al.  irradiata et al.  studied a et al.  observedTo investigate the effect of irradiation on mechanical properties, Liu et al.  establisTo characterize the effect of irradiation on embrittlement, Zhou et al.  comparedIn conclusion, nuclear pressure vessel materials with different microstructures have different irradiation properties. Irradiation can cause microstructure matrix defects, irradiation hardening and irradiation embrittlement, and the degree of irradiation hardening and embrittlement increases with the increase of irradiation doses. Generally, the matrix damage, Cu-rich cluster structures, Ni–Mn–Si-rich clusters as well as P, S segregation on grain boundaries were important factor for radiation embrittlement of nuclear pressure vessel materials. However, the clusters would decompose and the defects would recover during the annealing process, which was beneficial to improve the properties of the materials. Theoretically, nuclear pressure vessel materials are rarely in direct contact with corrosive solutions due to the austenitic stainless surfacing on the inner wall of nuclear pressure vessels. However, the actual operation experience of global nuclear power plants shows that the serious corrosion behavior of RPV materials caused by the leakage of boric acid water in the primary circuit is common ,77. TherAccording to the operating experience of PWR nuclear power plants in the world, the corrosion behavior of nuclear pressure vessel materials caused by boric acid leakage could be divided into the following two types ,78,79: F2O3 at low temperature, while the corrosion products were favorable to the formation of Fe3O4 at high temperature. The adhesive strength of latter with interface was higher than that of the former, which protected the material and decreased the corrosion rate to very low values even at high temperature.In the service environment of nuclear pressure vessel, the boric acid concentration and temperature were the main factors affecting the compactness of passivation film of low-alloy steel. Xiao et al.  found thAt present, it can be determined that the corrosion rate of nuclear pressure vessel materials increases with the increase of boric acid concentration, but there are different views on the influence of temperature on its corrosion rate. In addition, the research reports on the corrosion resistance of nuclear pressure vessel materials are not systematic. The structure of passive film, the formation and destruction mechanism of passive film, and the anti-corrosion measures are not clear. Therefore, in order to ensure the long-term safe service of nuclear pressure vessels, the research on corrosion resistance of nuclear pressure vessels materials needs to be focused on in future research work.Thermal aging refers to a phenomenon that the microstructure of material will change under high temperature environment for a long time, and then lead to changes in the properties. Long term service of RPV materials in high temperature environment can easily cause thermal aging embrittlement.The thermal aging embrittlement of low-alloy steel is closely related to thermal aging time and temperature. Druce et al.  studied It can be seen that the long-term thermal aging may not have a significant influence on mechanical properties but has a great influence on the ductile–brittle transition temperature. Generally, the ductile–brittle transition temperature of RPV materials increases significantly with the increase of thermal aging time.Fatigue damage accompanied the whole service cycle of RPV, and it mainly includes two influencing factors: Material factors and environmental factors, also known as internal and external factors ,88,89,90The influence of microstructures structure, inclusions, carbides and HAGBs on the fatigue properties of nuclear pressure vessel materials are internal factors. Jang et al.  studied The new generation of RPV pay more attention to safety and service life compared with the previous RPVs materials, so the forging size and wall thickness of SA508Gr.4N steel were greatly increased ,102. TheThey  followedThe loading waveform of fatigue test can be divided into triangle waveform, sinusoidal waveform and positive sawtooth waveform, and so on. The difference of waveform will lead to the difference of fatigue properties. Achilles et al.  studied Huang et al.  investigIn addition, the loading frequency and strain rate also had great influence on the fatigue properties of nuclear pressure vessel materials. Tice  investigThe effects of carbides, HAGBs and microstructure evolution on fatigue properties are internal factors. Fine carbides and HAGBs can hinder fatigue crack propagation and increase the fatigue life of materials. The effects of strain amplitude, service environment and loading frequency on fatigue performance are external factors. The increase of strain amplitude and corrosive environment will decrease the fatigue life of materials.In this review, we have summarized the research progress of nuclear pressure vessels from different perspectives, including the development of RPV materials, service environment, microstructure evolution, mechanical properties after forging, as well as the effect of service environment on RPV materials. Based on the improvement of nuclear power safety and economy, nuclear pressure vessels had developed from the early plate welding structure to the present large-scale integrated forging structure. The low-temperature and high-temperature forging process were not conducive to the uniformity of the microstructure of the material after forging. Therefore, the selection of forging parameters was very important for the subsequent materials properties before the application of nuclear pressure vessels. The ASTM standard specified that nuclear pressure vessels must meet certain performance requirements after forging. The alloying elements, heat treatment parameters determined the mechanical properties of materials by changing the microstructure structure, grain size, carbides size and large angle grain boundary volume fraction.In addition, nuclear pressure vessels had been used in harsh environments such as neutron irradiation, corrosion, high temperature thermal aging and fatigue damage for a long time, which would deteriorate the properties of RPV materials. Nuclear pressure vessel materials exposed to neutron irradiation for a long time would cause matrix damage, dislocation loops and impurity element segregation, resulted in irradiation hardening and irradiation embrittlement. Although stainless steel was overlaid on the inner wall of the nuclear pressure vessel to prevent corrosion of its materials, long-term service might lead to damage of stainless steel and leakage of potential leakage sources, which would lead to directly contact between the RPV materials and boric acid corrosion solution, and then cause the occurrence of corrosion behavior. Long-term service at high temperature would cause thermal aging behavior of RPV materials, which would lead to microstructure decomposition or carbides coarsening. The thermal aging behavior mainly caused the increase of the ductile–brittle transition temperature and deteriorated the impact properties of materials. Finally, fatigue damage also accompanied the whole service process of nuclear pressure vessels. The influence factors of fatigue included microstructure evolution, second phase, service environment, corrosion environment and strain rate, etc. The fine second phase could hinder the propagation of fatigue cracks, while the coarsening second phase would become the source of crack initiation. In addition, corrosion fatigue would significantly decrease the fatigue life of materials compared with fatigue in air.At present, the research on the nuclear pressure vessel is mostly the influence of a single factor, such as radiation, corrosion and fatigue. However, the service environment of nuclear pressure vessels is very complex, and the influence of single factor on the performance is far from the real service conditions, so the research results are insufficient and unscientific for the safety application of RPV materials. Therefore, in order to ensure their safe service in the later period of service, the collaborative mechanism of multiple service environments on nuclear pressure vessel materials should be focused on studied in future work.


Recent advances in surgical techniques and perioperative management lead to a redefinition of the actual frontiers of Laparoscopic Liver Resection (LLR) by including patients with more advanced disease. Nonetheless, because of both underlying liver conditions and technical difficulty, LLR for Hepatocellular Carcinoma (HCC) is still considered as a challenging procedure. Specific concerns exist about LLR in cirrhotic patients, posterosuperior segments, giant and multiple tumors, as well as repeat resections. This review focuses on the specific limits of this approach in HCC patients in order to put into practice all the pre- and intra-operative precautions to overcome their boundaries, making this technique the standard of care within high-volume hepatobiliary centers.The minimally invasive approach for hepatocellular carcinoma (HCC) had a slower diffusion compared to other surgical fields, mainly due to inherent peculiarities regarding the risks of uncontrollable bleeding, oncological inadequacy, and the need for both laparoscopic and liver major skills. Recently, laparoscopic liver resection (LLR) has been associated with an improved postoperative course, including reduced postoperative decompensation, intraoperative blood losses, length of hospitalization, and unaltered oncological outcomes, leading to its adoption within international guidelines. However, LLR for HCC still faces several limitations, mainly linked to the impaired function of underlying parenchyma, tumor size and numbers, and difficult tumor position. The aim of this review is to highlight the state of the art and future perspectives of LLR for HCC, focusing on key points for overcoming currents limitations and pushing the boundaries in minimally invasive liver surgery (MILS). Liver cancer is the fifth-most-common cancer in the world and the fourth-most-common cause of cancer-related death . With anSince the first laparoscopic liver resection (LLR) was reported by Reich and colleagues in 1991 , its sprIn the setting of hepatocellular carcinoma (HCC) treatment, international guidelines have officially approved the use of laparoscopy in the treatment of early-stage disease ,11. IndeHowever, several limitations to the universal adoption of LLR for HCC still exist. Firstly, the minimally invasive liver surgeon must be confident with both laparoscopy and open liver surgery. Secondly, there is the need for performing more complex procedures than for other liver pathologies, which includes anatomical resections (AR), thanks to the theoretical advantage of excising the entire primary tumor along with adjacent liver parenchyma containing micro-metastases, even if survival advantages are still debated ,15. FinaIn this review, we will first summarize the current indications and limitations for LLR for HCC, and then we will focus on the strategies for overcoming the current challenges.Several advantages have been proven in patients undergoing minimally invasive surgery in other surgical fields, including reduced length of hospital stay, postoperative pain, bleedings, complication rates related to surgical incision, and improved postoperative quality of life. However, after 30 years since the first reported LLR, a randomized trial testing the efficacy and safety of a laparoscopic approach for HCC treatment still does not exist. To date, only one randomized controlled trial investigating LLR has been published, the OSLO-COMET, focused on patients with colorectal liver metastases undergoing parenchymal-sparing liver surgery, therefore including mainly atypical resections in non-cirrhotic patients, showing reduced postoperative complications and hospital stay in the laparoscopic group .Even in the absence of randomized trials, recommendations for implementation and adoption of LLR in HCC were proposed by expert consensus conferences, then followed by recent guidelines based on non-randomized studies. The first international expert consensus was held in Louisville in 2008 . This coThe Southampton Consensus Guidelines 2018) can be considered the actual clinical practices guidelines, aiming to guide “the safe development and progression of laparoscopic liver surgery”  can be c,20. FurtThus, the adoption of LLR for HCC should now be recommended in each high-volume HPB center. During the initial phases, clinical practice should follow a step-wise approach, starting from minor liver resection in anterolateral segments, followed by major liver resections and resections of lesions located in posterosuperior segments, which are the most difficult due to the orientation of the transection planes. To guide this approach, several difficulty scores and classification systems have been described. Unfortunately, to date, most of the available scores consider only some aspects, and there is not a score able to predict all the different possible outcomes.Even after the consensus statements, the role of LLR in some situations is still debated, such as for difficultly located HCC and for multiple or giant lesions.In the near-zero mortality era, with all technological advances available in surgical, anesthesiologic, radiological, and hepatological fields, attention must be focused not only on intraoperative aspects but also pre- and postoperative assessments. Meticulous preparation of the patient, with attention to every aspect concerning the different phases of management, is the key to finally overcoming different limits in the treatment of HCC patients.One of the most important differences from other surgeries is that liver resections need a wide preoperative evaluation with very tailored surgical planning. A precise study of our patient’s anatomy, as well as the exact location of the lesion within the liver and its relationship to vascular structures, is essential to correctly plan LLR. Anatomical and positional aspects seem to be even more important in HCC surgery, given the importance of performing anatomical resections, which implies the removal of the entire portal territory nourishing the tumor, which could be associated with better short-term oncological results ,22. TherStandard = LRV/TLVStandard × 100%) [When dealing with large resections, especially in the case of cirrhotic liver, multiple tumors, or large-sized lesions, the risk for post-hepatectomy liver failure (PHLF) is still an important cause of mortality . The pre × 100%) . It is c × 100%) .Stratification in cirrhotic patients always has to be assessed using the Child–Turcot–Pugh (CTP) and the Model for End-Stage Liver Disease (MELD) score, as recommended in international guidelines ,11. In pThe measurement of indocyanine green (ICG) clearance is widely performed in Asia, as well as in high-volume Western HPB centers. It is a dynamic method that evaluates the hepatic clearance of indocyanine green 15 min after its intravenous administration (ICG-R15), and it is usually delayed in cases of liver disease . A decisHepatobiliary scintigraphy with 99mTc-mebrofenin (HBS) is the most widely used nuclear medicine imaging technique to assess liver function. The 99mTc-mebrofenin extraction rate is correlated to underlying parenchymal status and to ICG clearance (sharing the same OATPB1/B3 transporters) . In addiWhen needed, different strategies can be used to induce compensatory hypertrophy of FRL to reduce the risk of PHLF. To date, portal vein embolization (PVE) is considered the standard of care procedure for the FRL augmentation, with indications that include HCC on the cirrhotic liver. Up to 85% of patients can undergo liver resection after 4–6 weeks, which means that there is almost a 20% of failure rate due to both insufficient FLR or tumor progression in the waiting time . To prevGuiu et al. proposed the liver venous deprivation (LVD) technique, based on the simultaneous embolization of the hepatic vein (± the median) and the ipsilateral portal vein, with an amplatzer plug positioned at about 10 mm from the ostium . PrelimiAssociated liver partition with portal vein ligation for stage hepatectomy (ALPPS) is a two-staged hepatectomy (TSH) firstly described by Schnitzbauer et al. in 2012, with the main advantage of sensitively reducing the delay among first and second procedures . The maiAccording to different international guidelines, preoperative portal hypertension should be assessed in cirrhotic patients undergoing liver resections ,44. The Furthermore, even if liver resections in patients with portal hypertension have traditionally shown high morbidity, thanks to ongoing improvements in surgical technique and intensive care management, they are considered feasible in selected patients in high-volume centers, leading to suitable long-term results, especially after LLR ,48. AzouThanks to developments in surgical and anesthetic techniques, high-volume centers have reported operative mortality for LLR of less than 5% . HoweverLLR carries an important risk of blood loss for the dissection of the hepatic vein, inferior vein cava, portal vein, and the transection of a highly vascularized parenchyma. Increased blood loss and perioperative blood transfusions are associated with worse perioperative morbidity and mortality . Both suAir embolism is another known intraoperative complication of LLR that can result from the use of pneumoperitoneum, with various precautions that have been proposed to reduce this risk. However, more recent evidence showed no increased risk of air embolism during LLR compared with OLR, neither depending on patient positioning .HCC develops in a cirrhotic liver in approximately 80–90% of cases, and the incidence of cirrhosis is expected to increase worldwide due to the prevalence of obesity, fatty liver disease, and alcoholic steato-hepatitis . After aWhen considering liver resection in patients with liver cirrhosis, it is important to consider not only the oncological outcomes but also the surgical stress on both the patient and the liver. An important consequent advantage of LLR in cirrhotic patients is the lower incidence of postoperative liver failure and ascites, given the reduced interruption of portosystemic shunts and the avoidance of electrolyte imbalances as a result of the exposure of the abdominal content to the air . FurtherIn the first years of the spread of LLR, huge-volume tumors were considered a contraindication due to both technical and oncological issues. The last decades saw an extension of tumor burden-related indications for LR. Currently, the EASL guidelines recommend LR in cases of a resectable lesion regardless of its size, while the AASLD guidelines advocate LR in patients with Child–Pugh A cirrhosis and resectable HCC with a diameter less than 5 cm. Meanwhile, according to APASL, all tumors without extrahepatic metastases are potentially resectable regardless number and size of lesions ,11,44. HRecently, Hong et al. published suitable long-term outcomes from a nationwide cohort of 466 patients with large HCC, suggesting a worse prognosis in subgroups with low platelets and tumors >10 cm . SimilarGiant tumors indeed are extremely demanding to operate on, where limits of what is considered technically feasible can easily be reached. The placement of trocars, the mobilization of a liver lobe, and the accidental tumor perforation by shear forces are examples of possible intraoperative difficulties. Further arguments against the laparoscopic procedure for giant tumors include that conventional recovery bags are too small, and a comparatively long incision is required to retrieve the specimen. In this respect, the question of feasibility depends primarily on whether the resection can be performed safely, and, if technically feasible, well-known advantages of LLR have also been confirmed in the literature for giant tumors .Therefore, the decision whether to operate laparoscopically or rather conventionally open should be based on the findings and, again, on the own learning curve and personal experiences made. In our experience, the trocars’ positioning is fundamental, and it depends on both the experience of the surgeon of the center, as well as on the segment to be resected. The manipulation of the liver must be performed with caution, using protections under the hepatic retractors so as not to damage the tumor capsule. The mobilization of the liver can also be performed laparoscopically in the case of large tumors, in which case the correct trocar positioning and the experience of both the surgeon and the operator that holds the rotating camera are once again important.Besides giant tumors, the role of LLR in the case of multiple HCCs is also debated. From an oncological point of view, in Western countries, the best candidates have always been defined as those with a single tumor, and the treatment of multifocal non-metastatic HCC consisted of LT, within Milan criteria, or ablation/chemoembolization for the remaining patients . As earlObviously, published data come from the long experience of high-volume centers for complex LLR. In our experience, an expert ultrasonography-guided parenchymal dissection is indispensable . Three-dIn conclusion, LLR should be considered in multinodular HCCs, but more robust studies are needed to support clinical practice. A personalized strategy can also be proposed, combining both laparoscopic ablation and resection when technically demanding, and the size and position of the lesions can benefit from it .The technical difficulty associated with LLR is linked to different aspects, such as parenchymal transection, hemostasis at the transection plane, and limited ability to explore deep and posterior regions of the liver. Therefore, LLR was initially reserved for superficial or left-sided lesions. The successive improvements in laparoscopic techniques and the introduction of new technologies mean that LLR is technically feasible in postero-superior (PS) segments , too  Figure . LLR of At the same time, improved laparoscopic techniques, better visualization of the operative field using a flexible laparoscope, and routine use of an ultrasonic cavitron for transecting the deeper portion of the liver parenchyma have allowed to reach excellent outcomes for LLR for HCC located in the PS segments, resulting in reduced blood loss, fewer complications, and shorter postoperative hospital stay compared with OLR tor the same segments in retrospective studies ,73. An iSegments 7 and 8 are the more posterior ones, rated as 5 on the Iwate score, because of unfavorable working angles and a poor operating view, especially with the classic trocar positioning, from caudal to cranial. Thus, different approaches have been proposed: Morise proposed a left lateral position for posterior sectionectomy and the semi-prone position S7 segmentectomy, with or without an intercostal placement or a lateral positioning of the trocars . Newer dIn our experience, it is the surgeon’s ability to master both hepatic anatomy and laparoscopic liver surgery that makes the difference, with the need to know how to deal with any dangerous bleeding from the hepatic veins and probably know when to convert to prevent them happen. The approaches described in the literature can probably all be used indifferently but consistently with the experience of the surgeon and the center. Finally, also for the resections of the PS segments, and perhaps above all, technology can once again come to our aid for the resections of patients with HCC. In fact, the use of the ICG allows obtaining both a positive and a negative counter-staining, facilitating the transection line in the Glissonian approach for anatomical resections, as originally described by Takasaki, useful specifically for HCC treatment ,76. At tAs already mentioned, HCC has a high risk of recurrence after both LT and liver resection. Thus, repeat laparoscopic liver resection (RLLR) has increased thanks to the progressive wide adoption of LLR. Furthermore, LLR reduces the risk of further adhesions. Kanazawa et al. showed that the operation time for RLLR after previous LLR was significantly shorter than after OLR . Belli eFinally, Morise et al. recently published an international multi-institutional propensity score-based study of RLLR for HCC, showing less blood loss and hospital stay for the laparoscopic group, even if the LLR was preferred for patients with favorable tumor characteristics .Since the first series of robotic liver resections (RLR) reported by Giulianotti et al. in 2003, different advantages of this approach have been proposed: from the ability to articulate the instruments and the magnified three-dimensional vision to ergonomic advantages for the surgeon ,83. SeveSafe and effective RLR for tumors located in the PS segment has been reported by several authors . SimilarThe high cost of treatment, as well as logistic and organizational aspects, may be the biggest shortcomings in the development of robotic surgery.Since the first laparoscopic hepatectomy (LDH) for a living donor LT (LDLT) was performed for a pediatric recipient by Cherqui in 2002, many transplant centers worldwide have adopted this approach, even if some concerns about donor safety still exist . Hong etSimilarly, the first robotic donor hepatectomy was a right hepatectomy reported by Giulianotti et al. in 2012, with the aim of applying the supposed advantages of the robotic approach also in the field of LT . The firFinally, what seemed to be the major limitation for laparoscopic liver surgery, namely the implantation of the liver graft in the recipient, was also overcome in 2021, a historic event for LT. The operation carried out by Suh et coll. lasted 960 min, including pure laparoscopic total hepatectomy and pure laparoscopic implantation, through a suprapubic incision, and was shown to be safe, without postoperative complications . FurtherIn conclusion, with the advances in surgical techniques and perioperative management experienced in the recent two decades, indications for LLR in HCC patients have tremendously improved and become technically practicable for the biggest part of lesions. Current advances in both surgical and medical treatment for HCC will probably redefine the actual frontiers of LLR by including patients with more advanced disease. With the exponential growth of LLRs performed around the world, it is important to know the specific limits of this approach in HCC patients in order to put into practice all the pre-, intra-, and postoperative precautions to overcome them, making this technique the standard of care within high-volume hepatobiliary centers. Expertise and learning curve should remain the mainstay, and the selection of appropriate candidates with meticulous preparation are the key points to ensure the success of the approach.


Tear fluid forms the outermost layer of the ocular surface and its characteristics and composition have been connected to various ocular surface diseases. As tear proteomics enables the non-invasive investigation of protein levels in the tear fluid, it has become an increasingly popular approach in ocular surface and systemic disease studies. Glaucoma, which is a set of multifactorial diseases affecting mainly the optic nerve and retinal ganglion cells, has also been studied using tear proteomics. In this condition, the complete set of pathophysiological changes occurring in the eye is not yet fully understood, and biomarkers for early diagnosis and accurate treatment selection are needed. More in-depth analyses of glaucoma tear proteomics have started to emerge only more recently with the implementation of LC-MS/MS and other modern technologies. The aim of this review was to examine the published data of the tear protein changes occurring during glaucoma, its topical treatment, and surgical interventions. Tear fluid is a dynamic and complex fluid forming the outermost layer of the ocular surface. It is an optimal sample material for proteomics research for many reasons; it contains over 1500 measurable proteins ,3, it caThe tear fluid is commonly considered to consist of three layers: mucin, aqueous, and lipid layers A. The inThe tear fluid provides protection, nutrients, and oxygen to the underlying avascular tissue and removes waste from the ocular surface, thereby reflecting the health, disease, and recovery of the eye in many ocular diseases ,6. SeverAs tear fluid can be used to study both ocular surface-affecting diseases as well as systemic diseases, it is no surprise that glaucoma, which is a collection of multifactorial diseases of the eye, is also being studied this way. Glaucoma is known to cause degenerative damage to the optic nerve and the loss of retinal ganglion cells (RGCs) B, resultThe most common forms of glaucoma are open-angle glaucoma (OAG), normal tension glaucoma (NTG), and angle-closure glaucoma (ACG). The glaucoma subtypes can be further categorized based on the pathological causes into primary and secondary , based on the age of the patient into adult, juvenile, and congenital forms, and based on the disease progression into chronic and acute forms. The wide selection of subtypes makes glaucoma research more challenging and currently, many studies focus on the most common forms of glaucoma .The presence, severity, and progression of glaucoma are currently established through clinical examinations. In addition to IOP measurement, the visual field, nerve fiber layer of the retina, optic disc, anterior chamber angle, and other alterations of the eye structures are examined by an ophthalmology expert . GlaucomCurrently, the pathophysiological changes of the different glaucoma subtypes as well as the effects of glaucoma treatment are being studied using a broad selection of research methods. In the genomics field, clinical researchers are trying to identify the genetic risk factors affecting glaucoma development ,17,18. ITear fluid samples can be taken in various ways, but Schirmer strips and capillary tubes are the two most common methods currently in use. In relation to tear proteomics, the most notable difference between these two sampling methods lies mainly in the protein types and protein numbers generated. The Schirmer strip, which is a filter paper placed under the lower eyelid, produces a higher number of quantified proteins and proportionally a higher number of proteins of an intracellular origin, whereas capillary tube samples generate proportionally more secreted and extracellular proteins . There iOver the years, different technologies including two-dimensional electrophoresis (2-DE), large-scale western blotting, and antibody microarrays have been used in proteomic analytics . HoweverDuring the last decade, there have been significant improvements in mass spectrometry (MS), which can be implemented in the global analysis of all the proteins in a sample. These improvements include more advanced MS instruments, the added advantage of the hyphenating MS to separation techniques, e.g., liquid chromatography (LC), and the ability of tandem mass spectrometry (MS/MS) for peptide and protein structure elucidation. These advances mean that MS-based proteomics has become one of the most frequently chosen analytical methods for qualitative and quantitative investigation of complex protein samples ,27 and iOne of the main pitfalls of the MS techniques in tear proteomics is connected to the fact that the aqueous layer contains several high abundance proteins, referred to as major tear proteins, including albumin (ALB), lysozyme (LYZ), and lactotransferrin (LTF). These high-abundance proteins result in a wide dynamic range of proteins, making the detection of lower abundance proteins challenging . Other possible approaches to studying tears are also emerging. The study of microRNA ,30 can pIt is important to recognize that the selection of sampling methods, analytic technologies, and study population will have a great effect on the results. For the same reason, comparisons between studies can be challenging. For example, the age of the study population has been established to affect the tear protein levels . TherefoIn relation to glaucoma, the tear fluid is located far from the original site of damage, i.e., RGCs and optic nerve, but the tear fluid’s proximity to aqueous outflow channels, i.e., trabecular meshwork, Schlemm’s canal, and episcleral veins, could be beneficial as they are connected to the pathophysiological changes in glaucoma. In the following sections, we will also discuss how the tear fluid is closely connected to topical treatment effects as well as glaucoma surgery outcomes.In order to understand the effects of individual tear proteins, it is important to understand how glaucomatous changes affect the tear fluid and other anterior parts of the eye. In many of the common glaucoma subtypes, as the normal aqueous humor outflow is disrupted, increased IOP and changes in the normal function of the eye can lead to biomechanical, vascular, and immune-related stress. This stress is thought to further lead to mitochondrial dysfunction, chronic oxidative stress, and the generation of reactive oxygen species (ROS), inducing RGC degeneration through inflammation, autophagy, and apoptotic pathways B 34,35,,35,36.E and identified 27 proteins, which differed in abundance between the study groups. The majority of the tear proteins, which differed significantly in this study, were upregulated among the glaucoma patients and included proteins associated with inflammatory response, free-radical scavenging, and cell-to-cell signaling and interaction. A similar study by Rossi et al. [Tear proteomics makes it possible to non-invasively study, how the aforementioned disease mechanisms affect and reflect on the tear fluid and ocular surface. A previous study by Pieragostino et al.  examinedi et al.  examinedi et al. ,48,49,50Many of the proteins identified as up- or down-regulated with both treatment-naïve and treated glaucoma patients in In addition to proteins, the level of homocysteine (Hcy), an amino acid, has been studied in tears in relation to glaucoma. Hcy is broken down by vitamins B6 and B12 and folic acid, and in the tear fluid, it has been identified to be elevated for both POAG and pseudoexfoliation glaucoma (PXG) patients ,53. The Due to the myriad combinations of glaucoma types, treatment status, and medications in use, it has been difficult to establish sensitive and specific tear biomarkers which could detect glaucomatous changes at the early stages of the disease progression. Therefore, more work is needed in glaucoma-related tear biomarker discovery if they are to be used as a part of clinical glaucoma diagnostics. Although other sample materials such as aqueous humor or tissues do require invasive sampling techniques, they could provide complementary information about the health status elsewhere in the eye and provide a more comprehensive insight into glaucomatous effects taking place in the eye.Since IOP is so far the only controllable pathophysiological mechanism of glaucoma, the treatment approaches focus on its lowering and control through increasing the outflow and decreasing the production of aqueous humor. It has been proven as an efficient treatment approach through multiple studies ,57,58. DAlthough the eye drops used to treat glaucoma are normally effective in lowering IOP, the prolonged use of topical glaucoma medications results in various changes in the anterior segments of the eye. These changes in the tissues include the loss of conjunctival goblet cells, Meibomian gland abnormalities, and structural changes to the ocular surface epithelium and they are often exacerbated by an increasing number of topical glaucoma medications as well as preservatives in the topical treatments ,60,61. IIn addition to the active ingredients of the eye drops, preservatives used in eye drops, especially benzalkonium chloride (BAK), are shown to be a major cause of adverse reactions, and often a switch to preservative-free medication alleviates these symptoms ,68,69,70It is worth noting that the ocular surface effects can further differ depending not only on the active ingredients used in the topical treatment, which include, e.g., prostaglandin analogues, beta-blockers, carbonic anhydrase inhibitors, cholinergic compounds, alpha agonists, and rho kinase inhibitors, but also the type of glaucoma being treated. The large selection of active ingredients and preservatives as well as their use in combinations can make the study of disease mechanisms and treatment effects particularly difficult. Some previous studies examining the effects of topical glaucoma treatment have limited their focus to specific glaucoma subtypes, such as POAG and PXG, and specific topical treatment types to ensure more homogeneous groups to compare.Pieragostino et al.  includedAnother study with POAG patients  identifiIn a study focusing on uveitic glaucoma patients, the treatment approaches  were compared against each other . In the Some glaucoma treatment studies have been less stringent with their inclusion criteria regarding either the glaucoma type or the active ingredients in their treatment. This way, more general findings of different effects of topical glaucoma treatment have also become available. Several cytokine studies have identified increased levels of many proinflammatory cytokines in tears of treated glaucoma patients, including interleukins , TNF, C-C motif chemokine ligand 2 (CCL2), vascular endothelial growth factor (VEGF), fibroblast growth factor 2 (FGF2), and IFNG ,76,77. IIn recent years, the study focus has shifted more towards the comparison of different treatment types. For example, a comparison between preserved and preservative-free eye drops is of interest now that the harmful effects of preservatives are better understood. Previous studies have examined the cytokine differences between patients receiving either preserved or preservative-free latanoprost medication. Martinez-de-la-Casa et al.  reportedBoth Funke et al.  and NättIf the progression of glaucoma cannot be controlled with medication alone, or if the patient experiences adverse effects, difficulties, or unwillingness to perform topical therapy, more invasive methods, such as laser and incisional surgeries can be performed. Usually, glaucoma surgery is performed on patients with a long history of topical medication use, although in certain conditions, such as ACG and very high initial IOP, glaucoma surgery can be the first therapeutic choice.A long history of continuous topical glaucoma medication prior to surgery, as well as the resulting ocular surface adverse reactions, have been found to negatively affect the ocular surgery outcome ,88,89,90There is a large variety of possible surgical techniques to choose from in glaucoma treatment. After Cairns introduced trabeculectomy in the 1960s , it has The main goal of all these surgical techniques is to improve and redirect the aqueous outflow either to subconjunctival or suprachoroidal space. This can be achieved by creating a new pathway for aqueous humor to escape from the eye, either by using the eye’s own tissues or by inserting biocompatible tubes in the structures of the eye. The success of these operations is highly dependent on the controlled wound healing, which will enable a stable outflow of aqueous humor and a low but sufficient IOP since an exacerbated wound healing is the most important cause of surgical failure .In relation to wound healing issues, it is further known that the preoperative state of the conjunctiva is one of the major risks leading to exacerbated wound healing and surgical failure, and for this reason, antifibrotic agents are frequently used in connection to the surgery ,89. Why In relation to tear fluid, previous clinical studies have found that postoperative tear fluid characteristics are associated with the morphologies of glaucoma filtering blebs created during filtration surgery . It is hMany of the previous tear proteomics studies have attempted to identify tear proteins, which could indicate surgical failure prior to surgery. Chong et al.  identifiIn addition to studies examining the potential predictive biomarkers for trabeculectomy failure, some studies have also extended their research to clinical variables and protein level follow-up. Burgos-Blasco et al.  identifiAlthough many interesting studies have already examined the glaucoma surgery outcome biomarkers in tear proteomics, more research is needed to better understand the biological processes occurring during glaucoma operation failures. In order to achieve this, more longitudinal studies are necessary. Studies spanning over several years not only help us understand and stratify the surgery outcome failures further but also help us gain a deeper knowledge of the effects of prolonged use of topical glaucoma treatment and its cessation. The majority of the tear proteomics studies so far have focused on studying the effects and outcomes of the trabeculectomy method, and less attention has been paid to other surgical approaches. Therefore, studies focusing on other surgical methods, as well as comparisons between these methods, are needed to enable a more personalized treatment approach for glaucoma surgery patients.As is the case in many diseases, the current research aims to provide more targeted and personalized treatment options for patients in the future, and glaucoma is no different. In glaucoma, this is particularly needed due to the difficulties related to both topical medication and glaucoma surgery, such as high risks of adverse events and low compliance in topical treatments as well as surgical failures. Although the multifactorial nature of the disease is becoming better known, treatments still focus solely on the control of the IOP. A better understanding of the disease mechanisms at both molecular and pathway levels in different glaucoma subtypes can help in the development of the targeted treatment methods in the future.Currently, potential diagnostic and therapeutic targets, i.e., biomarkers, have already been identified in various sample materials, including tears, but further development of these biomarkers into functional clinical tools is still in process. In addition, the attempts to discover a marker unique to, e.g., the topical treatment effects of glaucoma are still ongoing. Clinically available biomarkers could enable earlier detection of arising problems and the more straightforward initiation of medical therapy. In addition, a more individualized topical treatment selection would help reduce the risks of adverse effects, this way enhancing the compliance to treatment routine and patients’ well-being. Similar benefits would apply to glaucoma surgery as a mode of in-depth investigation of the ocular surface state prior to the surgery, and the assignment of personalized preoperative treatment could improve the chances of a successful outcome. During the surgery follow-up, the control of anti-inflammatory medication could be controlled based on the ocular surface state, and cascades leading to failure could be intervened early.Although the recent evidence demonstrates the potential value of tear fluid proteomics in glaucoma diagnostics, certain confounding factors such as the effects of therapeutic interventions should be recalled when inspecting the pathogenic mechanisms and progression of the disease. Since the tear reflects more precisely the health and changes taking place in the ocular surface, it can be debated whether changes, which are initially thought to occur in the retina and optic nerve region, can be observed in tear fluid alone. Instead, it is clear that tear proteomics can be a vital tool in understanding the effects of topical medications, as these do largely affect the health of the ocular surface. In future studies, more can be achieved when tear proteomics is combined with information obtained from other sample materials as well as extensive clinical and lifestyle information. A recent study by Pinazo-Durán et al.  implemenThe ocular surface and the dynamic role of tear fluid in regulating its sensitive homeostasis are directly affected by the medical and surgical interventions for glaucoma. Furthermore, tear fluid offers novel possibilities as a non-invasive liquid biopsy, which can enable the clinical diagnosis of various forms of glaucoma and the detection of the pathophysiologic mechanism involved in glaucoma development and progression. Although the history of tear fluid proteomics is relatively long, the recent development of modern technologies such as LC-MS/MS methods has enabled the production of proteomics data with hundreds of tear proteins and their associated abundance levels, enabling a more in-depth analysis of the biological functions and pathways underlying glaucoma. Together with an improved understanding of the role of the ocular surface in successful glaucoma care and rapid development of the medical and surgical therapeutic options, tear fluid proteomics offers a clinical tool to tailor the therapeutic strategies on individual bases. In the future, larger tear protein panels, possibly combined with other types of sample materials and powerful computational tools, could enable us to provide patients with more personalized treatment, all while also controlling the potential associated risks.


During major pandemics such as COVID-19, the fear of being infected, uncertain prognoses, and the imposition of restrictions may result in greater odds of emotional and psychological distress. Hence, the present study examines the predictors of psychological distress during the COVID-19 pandemic in Canada, and how they differ by gender.Data of 2,756 adults aged 18 years and above from a cross-sectional online survey conducted between July and October 2020 was used for this study. A multivariable logistic regression analysis was carried out. The results were presented as adjusted odds ratio (aOR) with their respective confidence interval (CI).Lower odds of psychological distress were found among males compared to females and among individuals aged 45–64 or 65–84 years compared to those aged 18–44. The odds of psychological distress decreased with a rise in income, with individuals whose annual income was greater than or equal to $100,000 being less likely to experience psychological distress compared to those whose income was less than $20,000. The odds of psychological distress were higher among residents of Ontario compared to residents of Quebec. Similarly, the odds of psychological distress were higher among individuals who reported experiencing COVID-19 symptoms compared to those who did not report any COVID-19 symptoms. The disaggregated results by gender showed that age, province, and self-reported COVID-19 symptoms had significant associations with psychological distress in both males and females, but these effects were more pronounced among females compared to males. In addition, income was negatively associated with psychological distress for both males and females, with this effect being stronger among males.Five exposure variables  significantly predicted the likelihood of reporting psychological distress during the COVID-19 pandemic in Canada. Clearly, there is an imminent need to provide mental health support services to vulnerable groups. Additionally, interventions and policies aimed at combating psychological distress during pandemics such as COVID-19 should be gender specific. On March 11, 2020, the World Health Organisation (WHO) declared the novel Coronavirus-2019, hereinafter referred to as COVID-19, a global pandemic . Soon, tIn Canada, the first case of community spread of COVID-19 was reported in March 2020, nearly two months after the very first confirmed case of the infection . ThereafDuring major pandemics such as COVID-19, the fear of being infected, uncertain prognoses, impositions of restrictions that infringe on the freedoms of people, are likely to result in greater odds of emotional and psychological distress . PublishBefore the COVID-19 pandemic, it was estimated that at least one in three Canadians would suffer psychological distress and other forms of adverse mental health outcomes during their lifetime, with those in socially and economically marginalised groups having the highest tendency to develop suboptimal mental health . These dAlthough there are several studies that shed light on the coping mechanisms that individuals have adopted to mitigate the effects of the COVID-19 pandemic on their overall mental health in Canada , 15, theWe conducted an online survey to collect data using the SurveyMonkey platform. This survey was cross-sectional in nature and adapted from a study by Canning et al. in the US . PermissIn this study, the outcome variable was psychological distress. To derive this variable, respondents were asked whether they had experienced the following mental issues within the past 2 weeks: (1) feelings of anxiety or feeling nervous; (2) not being able to stop or control worrying; (3) feeling down, depressed, or hopeless; and (4) little interest or pleasure in doing things. Feeling nervous or anxious and being unable to stop worrying were considered an indicator of anxiety, while feeling down, depressed, or hopeless and having little interest or pleasure in doing things were considered an indicator of depression. These questions were derived from the Patient Health Questionnaire-4 (PHQ-4) . The resThe exposure variables in this study were gender , age , province , race , highest level of education , total income in 2019 in Canadian dollars , number of household members , belonging to a minority group, and self-reported COVID-19 symptoms, with each symptom coded as a dichotomous variable indicating whether an individual had the symptom or not.Descriptive and bivariate analyses were performed using the Stata version 14 software . The descriptive analysis showed the weighted frequency and weighted percentage distribution of the respondents. The bivariate distribution of the categories of psychological distress across the characteristics of the respondents was also performed. Next, the multinomial logit model was used to assess the predictors of psychological distress. Both bivariate and multivariable logit models were estimated. The results were presented using coefficient plots. Finally, the results of the multivariable multinomial logit model were disaggregated by gender and presented using coefficient plots. All statistical significance was obtained at a 95% confidence interval. We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline in reporting the results. Both descriptive statistics and regression results used weights that were generated using the distributions of gender, age, and province from the Demographic Estimations program at Statistics Canada (StatCan) to have national representativeness. We computed sampling weight for each sex-age-province stratum. Specifically, for each sex-age-province stratum, the weight is equivalent to the ratio of the share (probability of selection) of this stratum in the Census and the share of the same stratum in the survey sample.The study was approved by the Office of Research Ethics and Integrity at the University of Ottawa prior to the data collection (OREI reference#: S-06-20-5911). Only persons who are residents of Canada and over the age of 18 were eligible to participate in the study. The survey tool had an implied consent that respondents had to read and accept before their participation in the study. All participants’ data were anonymised before analyses. Participation was voluntary and respondents had the right to skip any question that they deemed sensitive to answer.Even with the advancement of vaccines to control the COVID-19 pandemic, the disease continues to have social, economic, and health effects on thousands of Canadians. As such, it has become imperative to ensure that this pandemic does not result in yet another and greater health crisis—that of mental illness. Hence, understanding the predictors of poor mental health during the pandemic is critical for the protection and promotion of optimal mental health of the population. We, therefore, examined the predictors of psychological distress among the Canadian adult population in the early period of the COVID-19 pandemic. The descriptive analysis indicates that close to half of the respondents (49%) experienced mild to severe psychological distress.Our study also revealed the gender disparity in the experience of psychological distress during the pandemic. Compared to males, females had a higher likelihood of reporting psychological distress. This is consistent with the findings from a related study that examined factors associated with psychological distress amidst the COVID-19 pandemic . PreviouAnalogous to the findings of some related studies , 22, we Expectedly, respondents who earned higher income experienced a lower risk of psychosocial distress as compared to those who earned less than $20,000 in 2019. This result is in line with prior evidence showing a lower risk of anxiety and depression among Canadians who earned higher income or were expecting higher income during this period of the pandemic . Our stuCanadians who reported COVID-19 symptoms had higher likelihood of experiencing psychological distress than their counterparts. The result is not surprising, given that the study period coincided with the first wave of COVID-19 in Canada. The first wave of COVID-19 was characterized by abundant uncertainties. Individuals who reported COVID-19 symptoms were mandated to be quarantined and if tested positive for COVID-19, they had to be isolated to prevent further spread of the disease . This reIn addition, the analysis of the predictors of poor mental health during the pandemic disaggregated by gender suggests that the effects of age, province of residence, and self-reported COVID-19 symptoms on psychological distress were exacerbated among females compared to males. By contrast, the protecting effect of income was more pronounced among males compared to females. These differences might be mirroring the varied gendered roles that males and females perform in our society. Males earn more than females on average. Females are more likely to work in sectors that increase their exposure and vulnerability to pandemics such as nursing, childcare, and front-office jobs. In addition, most females have the responsibility of household chores, taking care of children, and taking care of the sick, which are in themselves physically and mentally burdensome.The findings from the present study have some useful implications. First, our findings that Ontarians were at higher risk of experiencing COVID-19 related psychological distress calls on the provincial government to prioritize the mental health of Ontarians just as they ought to prioritize their physical health. Also, our findings underscore the need to target vulnerable groups, that is younger individuals (18–44 years), individuals with lower income, and females in interventions aimed at combating mental illness during pandemics. Our findings also illustrate the urgency for the provincial governments and the department of health to provide continuous counselling to persons who experience COVID-19 symptoms. Finally, our analysis suggests that mental health interventions during pandemics should be gender specific.This study was successful at determining the determinants of psychological distress during the COVID-19 pandemic among the Canadian population. We applied appropriate weighting which ensured that our data was representative of the national population to increase the generalisation of our findings to the adult Canadian population. Yet, there are limitations that should be considered when interpreting our findings. Our study relied on self-reported data; hence, it is subject to recall bias. We did not include older adults in long-term health care facilities. As such, our findings are limited to the population outside of such institutions. Again, due to the cross-sectional nature of our study design, the effects of the socioeconomic and demographic variables on psychological distress documented in this study may not be causal.This study sought to examine the predictors of psychological distress during the COVID-19 pandemic using evidence from a web-based national cross-sectional survey in Canada. Being female, being of lower age, residing in Ontario, experiencing COVID-19 symptoms, and having lower annual income in 2019 were significant predictors of the likelihood of reporting psychological distress. Moreover, most of these effects differed by gender. We conclude that there is a need for Canada to commit substantial resources towards addressing the mental health issues of its most vulnerable population.S1 File(PDF)Click here for additional data file.S2 File(DTA)Click here for additional data file.