The stepped-care pathway (SCP) model has previously been found to be clinically effective for depressive disorder in some studies, but not all. Several groups have suggested that a stepped-care approach is the most appropriate in primary care. There is relatively little information, however, regarding which specific stepped-care pathway may be best. This analysis aimed to determine cost-effectiveness of a stepped-care pathway for depression in adults in primary care versus standard care (SC), treatment-as-usual (TAU), and online cognitive behavioural therapy (CBT).We conducted a randomized trial with 1400 participants and 12-week follow-up to assess the impact of the four treatment options on health-related quality of life and depression severity. Costs for the groups were calculated on the basis of physician, outpatient, and inpatient services using administrative data. We then calculated the incremental cost-effectiveness ratios using this information. Cost-effectiveness acceptability curves and incremental cost-effectiveness scatterplots were created using Monte Carlo simulation with 10,000 replications. A subgroup analysis was conducted for participants who screened as depressed at baseline.For all participants, TAU was the most expensive followed by CBT, SC, and SCP. QALYs were highest in SCP, followed by SC, CBT, and TAU. In the depressed subgroup, TAU was still the most expensive, followed by SC, SCP, and CBT, while QALYs were still highest in SCP, followed by SC, CBT, and TAU. The cost-effectiveness acceptability curves suggested that SCP had a higher probability for cost-effectiveness than the other three alternatives in all participants. In the depressed subgroup, CBT was associated with the highest probability of cost-effectiveness for a willingness-to-pay cut-off of less than approximately $50,000, while SCP was the highest at a cut-off higher than $50,000. There is considerable uncertainty around the cost-effectiveness estimates.Our analysis showed that even where there are no clinically significant differences in health outcomes between treatment approaches, there may be economic benefit from implementing the stepped-care model. While more work is required to identify the most clinically effective versions of a stepped-care pathway, our findings suggest that the care pathway may have potential to improve health care system value.NCT01975207. The trial was prospectively registered on 4 November 2013.The online version of this article (10.1186/s12888-019-2223-3) contains supplementary material, which is available to authorized users. Depressive disorder has one of the highest degrees of disease burden in established market economies such as Canada –4. This A potential approach to more effective depression management is to universally screen all adults attending primary care and communicate the screening results to the clinic staff for appropriate interventions and/or treatments , 8. WhenThere is also relatively little information regarding which specific stepped-care pathway may be best . We haveIn our previously reported study , the prihttps://clinicaltrials.gov/ct2/show/NCT01975207 Identifier: NCT01975207. Details on methods employed in the trial have been published previously )Despite the use of universal screening and an RCT to control some of the biases inherent in such research, we are aware that the present study has limitations. The first is a concern regarding methodology as discussed in our previously published study . ParticiThe fourth possible limitation is that implementation costs were not included in the economic analysis. There would be set-up costs for the stepped-care pathway, and excluding these costs would underestimate the total costs. However, since these additional costs would occur only during the program implementation period, their effect on the intervention’s overall cost-effectiveness is likely limited over the longer term. Finally, people with major depressive disorder experience higher rates of unemployment and other disabilities than their peers . This asThe present economic analysis finds that even where there are no clinically significant differences in health outcome, economic savings may arise from implementing the stepped-care model. As with previous studies, we found that individuals who had depression incurred greater health care costs than those who were not depressed. However, somewhat counter-intuitively, our results suggest that a more comprehensive stepped-care pathway may lead to significant savings in overall health care costs versus treatment as usual for the entire population, not only those who screened as depressed at baseline. These findings, if validated in other studies, could have major economic implications for health care systems. As stepped-care pathways have been increasingly adopted by clinicians and policy makers , 16, 22,Additional file 1:Table S1. Number of participants in the four treatment groups separated into depressed and non-depressed subgroups. (DOCX 207 kb)


Siderophores are low-molecular-weight metal chelators that function in microbial iron uptake. As iron limits primary productivity in many environments, siderophores are of great ecological importance. Additionally, their metal binding properties have attracted interest for uses in medicine and bioremediation. Here, we review the current state of knowledge concerning the siderophores produced by cyanobacteria. We give an overview of all cyanobacterial species with known siderophore production, finding siderophores produced in all but the most basal clades, and in a wide variety of environments. We explore what is known about the structure, biosynthesis, and cycling of the cyanobacterial siderophores that have been characterized: Synechobactin, schizokinen and anachelin. We also highlight alternative siderophore functionality and technological potential, finding allelopathic effects on competing phytoplankton and likely roles in limiting heavy-metal toxicity. Methodological improvements in siderophore characterization and detection are briefly described. Since most known cyanobacterial siderophores have not been structurally characterized, the application of mass spectrometry techniques will likely reveal a breadth of variation within these important molecules. Fe3+ either precipitates as ferric oxyhydroxides or is bound to a wide variety of organic ligands in a “ligand soup” [Cyanobacteria rely on iron as an essential cofactor for performing oxygenic photosynthesis and therefore have much larger iron requirements than non-photosynthetic organisms . As ironnd soup” . In largnd soup” ,6. Cyanobacteria have developed a number of strategies to survive under iron limitations. Coping mechanisms include remodeling photosynthetic complexes , use of 3+ with common metabolites [3+). This complex can then be transported inside the cell. The reduction of Fe3+ then facilitates its release, as siderophores do not typically chelate ferrous iron (Fe2+) nearly as strongly [As an alternative import strategy, many cyanobacteria excrete siderophores. Siderophores are biologically produced low-molecular-weight (400–1000 kDA) compounds with an extremely high affinity for iron. Produced by microorganisms to enable iron acquisition under iron-limited conditions, siderophores are widely distributed in bacteria and fungi, and are found in marine, freshwater, and terrestrial environments. Increased iron bioavailability can also be achieved by the complex formation of Feabolites  includinabolites ,13 and habolites . Typicalstrongly . Based ostrongly . These aIn this mini-review, we will synthesize the current state of knowledge regarding the structure, biosynthesis, uptake mechanisms, detection and biotechnological application of cyanobacterial siderophores. While phytoplankton’s photosynthetic activity is responsible for one third to one half of global carbon sequestration , the molAnabaena sp, strain PCC 6411 and 7120 [Bacillus megaterium [N-hydroxy-N-acetyl)-aminopropane residues. Hydroxamate-type siderophores appear to be the most common siderophore type in nature, being widely distributed in both bacteria  and fungand 7120 ,28. Schigaterium  and is b23 [Ferric iron chelation for schizokinen and synechobactin is thought to work by the siderophore forming a hexavalent octahedron with the two oxygens of the two hydroxamate groups, along with the α-hydroxycarboxylate groups of the citrate moiety  and polyketide synthase (PKS) or NRPS independent synthases (NIS). Citrate-based siderophores such as schizokinen and synechobactin are produced by the latter system, which will be briefly described here. While the NIS pathways function primarily in the synthesis of polycarboxylate siderophores, the synthesis of hydroxamates and mixed-type siderophores by NIS has also been shown, with the genetic components predominantly found in actinobacteria and proteobacteria . TypicalE. coli K-12 is considered prototypical, and bioinformatic analysis for NIS-produced siderophores is often based on a similarity to the iucA gene that was characterized in the aerobactin pathway [N-acetyl-N-hydroxylysine and citric acid to form N-citryl-acetyl-N-hydroxylysine. IucC mediates the addition of another N-acetyl-N-hydroxylysine to the citric acid moiety of N-citryl-acetyl-N-hydroxylysine to form the symmetric aerobactin molecule [The aerobactin biosynthesis of  pathway . In aeromolecule .N4-hydroxy-1-aminopropane, and two of these molecules are bound to citrate to form schizokinen [all0390, all0392, all0393, and all0394) in Anabaena sp. PCC 7120 with a similarity to the biosynthesis-genes for rhizobactin 1021 [all0390 is induced by iron limitation [There is currently no biochemically-substantiated biosynthesis pathway established for the cyanobacterial siderophore schizokinen. However, schizokinen is an intermediary product in the biosynthesis of another siderophore, rhizobactin 1021. (Rhizobactin 1021 is unrelated to the siderophore rhizobactin). The synthesis of rhizobactin 1021 is similar to the synthesis of aerobactin, as a hydroxylated and acetylated molecule is first combined with citric acid and the resulting product is combined with another hydroxylated and acetylated molecule to form a symmetrical siderophore. Rhizobactin 1021 is synthesized from l-glutamic acid and l-aspartic b-semialdehyde which combines to form 1,3-diaminopropane. Further hydroxylation and acetylation lead to izokinen . Since stin 1021 . Transcrmitation .Synechococcus sp. PCC 7002, IucA/IucB/IucC-family proteins have been identified in an 8-gene operon  [56Fe peaks that correspond with schizokinen have been found in growth-phase Synechococcus sp. PCC 7002, supporting this idea [While no study has looked specifically into the biosynthesis of synechobactins in to sidH) . The opeto sidH) ,53. The his idea .Siderophores have the capability of complexing with metals other than iron. This feature can be used by microorganisms either for the uptake of essential metals like manganese or zinc, or it can sequester toxic metals outside of the cell. Coordination-chemistry of siderophores with non-iron metals is in most cases underexplored as it is typically not investigated when new siderophores are discovered. In general, the metal binding of siderophores is governed by the hard-soft acid-base theory. In these terms, the hard oxygen atom donors of siderophores are not necessarily well suited to bind to softer metals like Cu(II) or Zn(II), leading to lower affinities . NeverthAnabaena sp PCC 7120, reducing the toxicity of the metal, while a siderophore-independent system appears to be largely responsible for iron uptake. Schizokinen thus appears to have a double functionality in this organism [Anabaena flos-aquae have been shown to inhibit the growth of the alga Chlamydomonas reinhardtii [In cyanobacteria, hydroxamate siderophores have been shown to bind to copper, and siderophore cycling may have a role in preventing copper toxicity ,55. Undeorganism . In anotnhardtii . The effSynechococcus elongatus BDU 130911 have been shown to complex with uranium [Anabaena oryzae produces a hydroxamate-type siderophore that can chelate Cd2+ even under iron-replete conditions [Complexation of siderophores with metals other than iron has raised interest in the use of siderophores for heavy-metal sequestration. This can be done by combining siderophore-producing bacteria with the growth of metal-resistant plants . Hydroxa uranium . Interesnditions .ortho-isomer of dihydroxybenzene.Catecholates are siderophores characterized by one or more iron-binding catechol moieties: the Salmonella typhimurium and Escherichia coli [3+ complexes, depending primarily on pH and iron concentration [+ complexes have remarkably high iron affinities, with enterobactin-Fe3+ having a stability constant of 1049 [The catecholate siderophore that has been studied in most detail is enterobactin, first isolated from hia coli ,62. Conshia coli . Catechontration ,65. The  of 1049 . Catecho of 1049 .Synechococcus strains, and in freshwater Anabaena-strains [Anabaena cylindrica [In cyanobacteria, catecholate-type siderophores have been discovered in both marine -strains ,36. The lindrica . Anachellindrica  and anaclindrica . Two estlindrica . At physlindrica , but whiPeptide-based siderophores such as anachelin are often produced by a combination of the systems combining NRPS and polyketide synthases (PKS). NRPS pathways are well studied as they form the biosynthetic basis of a wide variety of peptidic secondary metabolites ,72,73,742, several PKS modules—each with a potentially additional enzymatic capability—can be combined within a single protein, similar to NRPSs. These modules can also have an extended range of substrates, including propionyl-CoA and methylmalonyl-CoA [3+.Structural and functional similarities connect the evolution of polyketide synthases to that of NRPS and even closer to fatty acid synthases. However, while one fatty acid synthases repetitively add the two carbon skeleton from the C3 precursor malonyl-CoA under release of COonyl-CoA . The othYersinia pestis has been proposed [The three-part structure of anachelin is the result of a combination of NRPS and PKS synthesis pathways. A biosynthetic pathway for the peptide and polyketide part of anachelin inspired by the NRPS/PKS assembly of yersiniabactin produced by proposed ,79. It iortho-quinone before aza annulation results in the final anachelin chromophore. Full chemical synthesis of anachelin has been achieved by a biomimetic route [The final synthesis of the catecholate chromophore part of anachelin has attracted some interest due to the unique tetrahydroquinolinium chromophore. A C-terminal tyrosine is added to the precursor molecule and is subsequently converted to a dopamine derivative. Enzymatic oxidation by a tyrosinase into an ic route .Anabaena cylindrica PCC 7122 that is likely related to the synthesis of anachelin. In addition to NRPSs that correspond to the l-Thr-d-Ser-l-Ser structure, four candidate genes for the creation of the salicylate starter unit, 2 PKSs that could add malonyl groups, as well as a putative hydrolase coupled with other genes necessary for the creation of the catechol moiety have been assigned. The gene cluster additionally codes for a thioredoxin-like protein, a siderophore-binding protein and a siderophore receptor [A bioinformatic analysis has identified a cluster of 20 genes in receptor . Taken tKirchneriella contorta and Chlamydomonas reinhardtii [The tripartite structure of anachelin invites the question of the functionality of the polyketide fragment, as it does not seem to be directly involved in iron chelation. Anachelin exhibits an inhibitory effect on the growth of the competing green algae nhardtii . This efnhardtii .Pseudomonas aeruginosa, demonstrating the first case of covalent bonding between a substrate and the cell surface [E. coli-produced enterobactin [2 surface with a simple dip-and-rinse procedure [Siderophores interface with metal surfaces, which gives microorganisms an anchor to colonize these surfaces. The siderophore pyoverdine plays an important role in biofilm-initiation by  surface . Sideroprobactin  substantrocedure ,86. Simirocedure .Siderophore cycling has two components: (1) the export of siderophores and (2) the import of the iron-loaded siderophore . PresumaKnowledge of siderophore export, especially in cyanobacteria, is limited. Three different protein types are involved in the siderophore export process in various bacteria: the major facilitator superfamily (MFS), resistance nodulation and cell division (RND) superfamily, and the ATP-binding cassette (ABC) superfamily .Anabaena sp. PCC 7120. In this organism, the inner membrane MFS protein SchE  is required for the secretion of schizokinen, along with the TolC-like outer-membrane protein hgdD , with the two proteins likely working in tandem [The only characterized siderophore export system in cyanobacteria is that of n tandem .3+-loaded siderophores are transported across the inner membrane, often by ABC-transporters [The import of iron-loaded siderophores is broadly similar across many bacteria and is illustrated in sporters .3+ to Fe2+ by ferric siderophore reductases or by ferric-siderophore hydrolases [Once inside the cell, iron has to be removed from the siderophore. This can happen either through the reduction of iron from Fedrolases  or by thAnabaena sp. PCC 7120, the import of iron complexed schizokinen across the outer membrane is accomplished by two TBDTs, named the schizokinen transporter  [alr2581). Transcription data indicate that IutA2 is transcribed earlier in the iron starvation response than SchT [In 7, SchT)  and IutAhan SchT .all2585-all5047-all4056) for energy. The genes are upregulated under an iron limitation, while similar genes show distinct regulation pattern under other conditions. Additionally, deletion mutations of the genes show an iron starvation phenotype [The TBDTs are likely dependent on the inner membrane complex TonB3-ExbB3-ExbD3 . These genes are similar to FhuBCD in E. coli, where FhuD functions as a periplasmic binding protein, FhuB is a membrane-embedded transporter and FhuC is an ATP-binding protein. Interestingly, while all three genes are upregulated under an iron limitation, they are regulated independently, as fhuC responds differently than fhuB/D to changing copper and citric acid levels. The significance of this is not clear [In the periplasm, Fe-schizokinen is recognized and transported to the cytoplasm via the hydroxamate system FhuBCD , known as siderophore piracy. robactin  and the robactin ,93.Synechocystis sp. PCC 6803 is capable of utilizing both schizokinen and the unnamed siderophore of Anabaena variabilis ATCC 29413 and can grow with iron-siderophore complexes as their only source of iron. While reductive iron uptake is considered the primary means of iron acquisition for this organism, the genome of Synechocystis has been found to code for a singular tonB (slr1484) gene, which functions along with exbB1–exbD1  in apparently typical siderophore uptake [Synechocystis sp. PCC 6803 is dependent on TBDT SchT (sll1206), which is organized in a gene cluster along with the gene coding for the ABC-type transporter FecB1CDE (slr1316 to slr1319). This system is able to operate independently of the ferric and ferrous iron transporters that are presumed to be the main iron acquisition mechanisms in Synechocystis sp. PCC 6803 [Similarly, the non-siderophore-producing PCC 6803 .Synechococcus elongatus BDU 130911, filamentous heterocystous Nostoc calcicola BDU 40302, as well as the filamentous non-heterocystous cyanobacteria Phormidium valderianum BDU 140081 and Oscillatoria boryana BDU 141071 established that under iron limitation, all four of them produce siderophores [The number and structural diversity of siderophores produced by cyanobacteria are probably much higher than the low number that structurally characterized siderophores may imply. The phylogenetic and environmental distribution of known siderophore-producing cyanobacteria is shown in rophores . This stAnabaena sp. PCC 7120, Anabaena variabilis ATCC 29413 and Synechococcus sp. PCC 7002 have NIS been tentatively identified in available genomes, while NRPSs were identified in more than 50% of analyzed cyanobacterial genomes [Synechococcus elongatus PCC 7942, raising the possibility of false negatives. At any rate, it appears that the cases of schizokinen and synechobactins are not particularly representative for the biosynthesis of siderophores in cyanobacteria. While NRPSs and PKSs are prevalent in cyanobacteria, they are classes of enzymes that participate in the synthesis of many non-siderophore molecules [Anabaena sp. strain PCC 7120 [Nodularia sp. CCY 9414 [In terms of distribution between the two biosynthetic pathways for siderophore production, siderophores based on NIS do not seem to be widely distributed in cyanobacteria. Only in  genomes . Howeverolecules ,74. It iPCC 7120 . This siCCY 9414 . The strCCY 9414 .Anabaena catenula (UTEX 375) [Anabaena cylindrica NIES-19 [Anabaena cylindrica CCAP 1403/2A [Anabaena cylindrica Lemm. 1611—[Anabaena cylindrica Lemm. 7122 [Anabaena flos-aqua [Anabaena oryzae [Anabaena sp. PCC 6411 [Anabaena sp. PCC 7120 [Anabaena variabilis [Anacystis nidulans [Gloeocoapsa alpicola [Microcystis aeruginosa NPCD-1 [Microcystis sp. SPC804 [Nostoc calcicola BDU 4030 [Nostoc sp. CENA21 [Oscillatoria tenius [Oscillatoria boryana BDU 140791 [Oscillatoria quadripunctulata NPRG-1 [Phormidium autumnale UTEX1580 [Phormidium valderianum BDU 140081 [Synechococcus elongatus BDU 130911 [Synechococcus sp. PCC 6031 [Synechococcus sp. PCC 6908 [Synechococcus sp. PCC 7002 [Synechococcus sp. PCC 7942 [Synechococcus sp. WH 8101 [References indicating the presence of siderophores in TEX 375) , Anabaen NIES-19 , Anabaen 1403/2A , Anabaenmm. 1611—,24, Anabmm. 7122 , Anabaenlos-aqua , Anabaena oryzae , AnabaenPCC 7120 , Anabaenriabilis ,101,102,a NPCD-1 , Microcy. SPC804 , Nostoc BDU 4030 , Nostoc . CENA21 , Oscillaa tenius ,103, OscU 140791 , Oscillaa NPRG-1 , PhormidUTEX1580 , PhormidU 140081 , SynechoU 130911 , SynechoPCC 6031 , SynechoPCC 6908 , SynechoPCC 7002 , SynechoPCC 7942 ,104, Syn WH 8101 .Methodology development has allowed considerable improvements in siderophore discovery and characterization in recent years, as well as improvements in analyzing metal-ligand interactions in ocean water. Traditionally, the detection of siderophores has been based on chemical properties of the active group by assays such as the Csaky assay  and the For elucidating structural information of siderophores, nuclear magnetic resonance spectroscopy (NMR), X-ray crystallography and mass spectrometry methods have all been employed. Both schizokinen and synechobactin were originally characterized primarily by NMR spectroscopy ,34, but 40Ar16O+ interference with 56Fe and with the addition of oxygen to the sample carrier gas, which ensures the complete combustion of organic solvents. These and other measures lower the detection limits to 30–250 femtomoles for iron complexes [Direct detection of siderophores from seawater samples is hindered by low concentrations of both iron and iron chelators. One approach for the rapid screening of seawater samples makes use of HPLC–tandem inductively coupled plasma-mass spectrometry (HPLC–ICP-MS). Requiring minimal sample preparation, the method can quickly detect metal-ligand complexes . Signifiomplexes .Synechococcus sp. PCC 7002 [2 fragmentation patterns to structurally characterize the compounds. This combined methodology revealed the presence of synechobactin-variants with odd-numbered fatty acid tails, which previously went undetected by NMR-based methods.Combining different MS-methods allows sensitive detection, quantification, and characterization of organic-metal complexes. Using both inductively coupled plasma mass spectrometry (ICP-MS) and high-resolution electrospray ionization mass spectrometry (HR-ESI-MS) has been demonstrated in the detection and characterization of synechobactin from PCC 7002 . RunningIncreased speed and precision in determining siderophores has been achieved by a newly developed 21 T Fourier Transform Ion Cyclotron Resonance Mass Spectrometer (FTICR MS) in combination with electrospray ionization . In thisImaging mass spectrometry (IMS) by matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) has been used to evaluate the spatial distribution of cyanobacterial siderophores colonies grown on agar . This teConsidering the ecological significance of iron uptake by plankton, it is surprising that so few cyanobacterial siderophores have been characterized. As cyanobacteria are expected to be responsible for ~25% of marine primary production , identifSynechococcus sp. PCC 7002, which can likely be anchored to a membrane, voids the argument that siderophores impose an unrecoverable cost to cyanobacteria in ocean environments. Additionally, genetic analyses show that the IucA/IucC homologs used to produce synechobactin and schizokinen are not widely distributed in cyanobacteria. This makes it likely that the wide variety of marine cyanobacteria that produces hydroxamate-type siderophores do so in ways that are not well-represented by the research that has been done so far.Our review highlights the emerging understanding of cyanobacterial siderophores in the ocean environment, as freshwater species were mostly used to understand siderophore biosynthesis and siderophore cycling. The discovery of the synechobactins from The development and application of mass spectrometry techniques have significantly increased the ease with which siderophores can be identified and characterized to gain further insight into the distribution, physiology and structural characteristics. In recent years, cyanobacterial siderophores have been identified in studies with a focus on “proof-of-technological-concept”, rather than an interest in the biosynthesis and physiological role of the molecule as a target itself. Application of these technologies to non-model organism cyanobacteria will surely lead to novel compounds with ecological as well as technological significance. The unique structure of anachelin and the nascent applications based on this molecule demonstrate that the potential of cyanobacterial siderophores matches their ecological importance.


Physical activity after major cardiac surgery has been associated with length of stay, discharge location, risk of readmission, and functional change. However, in-hospital mobility is not currently assessed in a standardized way with nurse reports being the primary mechanism of tracking patient activity. Furthermore, it is unclear whether it is the total amount, frequency, or type of activity that is most important for improving patient outcomes post-surgery. To better understand the duration, frequency, and intensity of patient activity post-cardiac surgery, we conducted an observational study of 206 patients using a wrist-worn accelerometer and ankle-worn pedometer. Patients with lower levels of average daily pedometer-based ambulation in the first four days post-surgery, when compared to counterparts who ambulated more, had higher odds of a longer length of stay  or being discharged to rehab vs. home (OR=7.7 p=0.012), independent of age, race, bypass time, and EuroSCORE (cardiac surgery risk score). Engaging in an average of less than two bouts of accelerometer-derived activity lasting 5 minutes or more each day was associated with higher odds of having a longer length of stay  or being discharged to rehab vs. home . A slower speed of recovery during the first four postoperative days, characterized by a smaller increase in pedometer-based ambulation with each successive day, was also associated with higher odds of being discharged to rehab vs. home . Further research is needed to develop appropriate frequency and activity thresholds for use as intervention tools to improve patient outcomes post-surgery.


Lack of confidence in suturing/ligature skills due to insufficient practice and assessments is common among novice Chinese medical interns. This study aimed to improve the skill acquisition of medical interns through a new intervention program. In addition to regular clinical training, expert-led or expert-led plus artificial intelligence (AI) system tutoring courses were implemented during the first 2 weeks of the surgical block. Interns could voluntarily join the regular , expert-led tutoring, or expert-led+AI tutoring groups freely. In the regular group, interns (n=25) did not receive additional tutoring. The expert-led group received 3-hour expert-led tutoring and in-training formative assessments after 2 practice sessions. After a similar expert-led course, the expert-led+AI group (n=23) practiced and assessed their skills on an AI system. Through a comparison with the internal standard, the system automatically recorded and evaluated every intern’s suturing/ligature skills. In the expert-led+AI group, performance and confidence were compared between interns who participated in 1, 2, or 3 AI practice sessions.The end-of-surgical block objective structured clinical examination (OSCE) performance and self-assessed confidence in suturing/ligature skills were highest in the expert-led+AI group. In comparison with the expert-led group, the expert-led+AI group showed similar performance in the in-training assessment and greater improvement in the end-of-surgical block OSCE. In the expert-led+AI group, the best performance and highest post-OSCE confidence were noted in those who engaged in 3 AI practice sessions.This pilot study demonstrated the potential value of incorporating an additional expert-led+AI system–assisted tutoring course into the regular surgical curriculum. Suturing/ligature skills are among the most essential foundations on which all surgical skills are built. Development an unconsciously mastered suture skills need repeated practice and years of experience. Nonetheless, incoming interns have a much shorter time to practice suturing and therefore find it difficult to achieve sufficient levels of competence and mastery ,2. It isIn current study, our new intervention program provided additional suturing/ligature tutoring for novice interns who had not previously received the corresponding training. Specifically, the medical interns were offered tutoring using 3 different teaching techniques: regular clinical training (the regular group), regular training plus an additional expert-led tutoring course (the expert-led group), and regular training plus additional expert-led+artificial intelligence (AI) tutoring courses (the expert-led+AI group). The primary goal of this study was to compare the relative suturing/ligature skills of the 3 different groups of novice medical interns.Taipei Veteran General Hospital (Taipei VGH) is a medical center that is certified as the formal teaching hospital of National Yang-Ming Medical University. Currently, the curriculum at National Yang-Ming Medical University and Taipei VGH consists of 6 years of teaching, including 4 years of university teaching  and 2 years of clinical training , which are followed by 2 years of postgraduate residency and several years of sub-specialty residency training.In detail, the third and fourth  years are different from the first and second years (basic common course) because they emphasize pre-clinical content, including skills associated with patient encounters, such as history taking, physical examinations, communication, self-directed learning, and problem solving. In the clinical years (internship), students participate in internal medicine, surgery, obstetrics and gynecology, and pediatrics blocks in fifth year and then primary care in their sixth year during clinical rotations.In the regular method of training suturing/ligature skills, before this new intervention program, medical interns learned their suture and ligature skills by chance from mentors during clinical rotations. Then, interns received feedback from experts after participation in their end-of surgical block formative objective structured clinical examination (OSCE). In the sixth year, medical interns need to develop their suturing/ligature skills continuously in order to pass their final summative OSCE before graduation. In this study, a new intervention program was implemented in the surgical block in the fifth year of clinical training by providing additional expert-led or expert-led plus AI tutoring for suture and ligature skills. The first (regular) group in this study received regular clinical training.This study received ethical approval from the Taipei VGH . Informed consent was given before participation in the study.Between November 2017 and December 2018, novice medical interns who had not received basic suturing/ligature skills training were invited to join this new intervention program. All interns from the classes of 2017 had the opportunity to voluntarily join either the expert-led tutoring (second) or expert-led plus AI (third) tutoring groups during their 3-month surgical block. The first group was interns who did not join either the second or third group; these individuals formed the regular group. Notably, medical interns in the 3 groups received similar regular clinical training in the surgical block. The first  group received regular clinical training, the second  group received regular training plus additional expert-led tutoring, and the third  group received regular training plus an expert-led+AI course. Notably, the duration of additional tutoring was similar between the expert-led and expert-led+AI tutoring groups .The common tutoring for both groups began with an orientation on how to suture/ligature on artificial skin by experienced experts  according to the objective structural assessment of technical skills (OSATS) criteria for the surgical OSCE. The suturing training kits contained a commercial needle holder, forceps, scissors, needle, silk, and a suturing pad. At the beginning of the tutoring course, the criteria for good suturing, including safety , quality (avoiding defects or errors in suturing or ligatures) and efficiency , were given as checklist to each intern. After 2 rounds of practice under expert supervision, following the criteria of the OSATS checklist, an in-training assessment was performed to evaluate the initial effects of expert-led tutoring. The OSATS checklist emphasized the technical performance (TP) score, including a 3-point  scale for the aforementioned criteria of safety, quality and efficiency as well as the global rating (GR) score . For each intern, the maximal TP and GR scores, which would translate into a 100% score, were 9 and 5, respectively. Finally, the expert concluded the teaching session by providing each intern one-on-one feedback according to their performance score at the OSCE station . It was In the expert+AI tutoring group, in addition to receiving a similar course to that of the expert-led group, every intern practiced their skills once on artificial skin that was connected to an AI recording and analysis system for suture/ligature training . Before practicing, each intern was required to watch the demonstration video. Within 1.5 hours, this AI training system automatically provided qualitative information about each intern’s TP score as a summation of 6 aspects including the skills of time , force in tissue (FoT), judging tension (JuT), equidistance (EqD), distance between sutures (DbS), and wound dehiscence (WoD). Notably, these 6 aspects covered the 3 domains of good suturing/ligature skills: safety , quality , and efficiency (T). Clearly, this system emphasized the safety and quality of suturing/ligature skills.In this study, the WKS-2RII system served as a self-assessment and training tool. The performance scores of each intern were calculated by comparison (percentage) with the performance of novice learners that had been set as the internal standard in the system. A total TP score greater than 70 was considered to be a passing score on the self-assessment, and a total score less than 70 was considered to be a failing score. Thus, every intern received their TP score and pass/fail data from the WKS-2RII system. Then, they used the data as the basis for a discussion with their clinical instructors.In addition to providing instructions on performing the task, the WKS-2RII system provided learners with images and reference parameters for experienced experts and novice beginners. Through independent practice, medical interns were able to compare their work with these internal standards. The WKS-2RII system served both as a tool for modeling steps of the task and as a reference for the desired outcome, facilitating self-directed learning.In addition to the minimal requirement of using the AI system for 1.5 hours, the interns in the expert+AI group were encouraged to utilize the AI (WKS-2RII) system as frequently as possible in order to enhance their suturing/ligature skills. The performance of those who had engaged in 1, 2, or 3 practice sessions with the AI system on the end-of-surgical block 1 station OSCE was compared.Ten weeks after enrollment in the study, the performance of the interns from the 3 groups was assessed through an end-of-surgical block formative OSCE using the same checklist as the in-training assessment. The TP and GR scores were assessed by experienced examiners.At the beginning of the in-training assessment and end-of-surgical block formative OSCE, raters discussed and agreed upon suturing/ligature criteria. A pilot study was conducted using 10 volunteer interns who each performed 3 single sutures.Using a 1-item questionnaire, self-assessed confidence on performing suturing/ligature skills on real patients was evaluated immediately after enrollment and at the end-of-surgical block OSCE with a 5-point Likert scale .Among the regular, expert-led, and expert-led+AI groups, this prospective comparative study evaluated the self-assessed confidence and performance of medical interns in performing suturing/ligatures at the end-of-surgical block OSCE.Data were expressed as mean±standard deviation. A significance level of P=0.05 was chosen. One-way analysis of variance was performed to compare the group characteristics and the assessment data of the regular, expert-led tutoring, and expert-led+AI tutoring groups.The basic characteristics of the interns in the 3 groups are shown in Notably, the percentage of interns with a baseline high level of interest in surgery was not significantly different across the 3 groups . MeanwhiAs shown in Suturing and performing ligatures are the most challenging basic skills for general practitioners in medical training. Repetitive deliberate practice is important for learning surgical and ligature skills . DetaileTypically, the basic instruction provided to medical interns focuses on performing ‘good’ sutures and ties on an OSCE. Without a suitable assessment system, it is difficult to instruct novice learners about which steps they do not do or about deviations from the standard procedure. In fact, some specific elements, including force in tissue, judging tension, equidistance between sutures, and wound dehiscence of sutures and ties, are difficult to check by direct observation of the task. In other words, those aforementioned details are not easily assessed with the OSATS criteria on an OSCE by the simple observation. In contrast, the AI system in our study separated the skills of suturing and performing ligatures into specific steps and highlighted all important steps. Therefore, medical interns were able to monitor their progress in developing these skills by using this AI system. Thus, the expert-led+AI tutoring course is an acceptable strategy for training medical interns in suturing and ligature skills. By engaging learners in the training, teachers can involve themselves in the educational program in different ways .According to the classic learning theory, detail information helps navíe students to learn complex task after efficient processing . MeanwhiA limitation of this study is that it was a small-scale pilot study only implemented at a single site. The performance of the medical interns in the regular group on the end-of-surgical block OSCE reflected the actual real-world learning of suturing/ligature skills. Additional tutoring, in either the expert-led or expert-led+AI tutoring group, will benefit medical interns in their surgical block. Therefore, the better performance of the expert-led and expert-led+AI tutoring groups may be attributable to the additional training these groups had in comparison with the regular group. Furthermore, in this study, interns voluntarily joined either the additional expert-led or the expert-led+AI courses. It is expected that these voluntary medical interns had higher motivation for learning than others. Therefore, it is possible that the better performance of the intervention groups might have at least partially stemmed from their higher intrinsic motivation for learning. Accordingly, the better performance of the expert-led and expert-led+AI tutoring groups reflects the combined effects of additional training and intrinsic motivation of the medical interns who joined those groups voluntarily.Interestingly, the generally low level of baseline confidence in suturing and ligature skills across the regular, expert-led, and expert-led+AI groups indicates that tutoring is necessary for interns. Additionally, the relatively poor performance of the regular group on the end-of-block surgical OSCE indicates that additional tutoring, either through an expert-led course or an expert-led+AI course, should be included in the regular curriculum.In conclusion, expert-led and AI-assisted tutoring is a feasible teaching method for novice medical interns, and yielded progressive improvements in their performance scores on suturing/ligature skills. Increasing the frequency of practice with the AI system improved medical interns’ confidence and performance in suturing/ligature skills. This study suggests that suturing/ligature tutoring should be implemented in parallel with real patient practice to increase medical interns’ confidence in suturing/ligature skills.


Deep ocean exploration was motivated by a series of scientific challenges to disprove previously widespread misleading ideas, such as that absence of life in ocean water or the seafloor at greater depths than certain limitations . It was Microbes and Environments have attempted to elucidate the compositional and functional diversities of microbial communities in investigations of previously unexplored deep-sea biotopes and microbial cellular and molecular components.Considerably later than the discovery and perception of deep-sea animal populations, psychrophilic and piezophilic microbial  populations were identified in deep ocean sediments , 28. In e.g., Candidatus Hydrothermaarchaeota” (Extremophilic microbial communities in deep-sea hydrothermal and seepage environments have been the most extensively studied among various deep-sea biotopes since their first discovery in 1977 e.g., , 12. Howchaeota” , origina2 respiration activities in many of the hadal trenches (Microbes and Environments (Sediments and water columns are two major habitats of deep-sea microbial communities. A number of bacterial strains have been isolated and described from deep-sea sediments . Howevertrenches , 9, 23. ronments –16. In aronments . On the ronments . These fShinkaia crosnieri, which dominates in the chemosynthetic animal communities of the Okinawa Trough deep-sea hydrothermal systems (Microbes and Environments, they showed that the epibiotic microbial community composition and metabolic functions varied in response to a shift in energy source availability during the laboratory rearing of host animals (Planktonic and benthic free-living microbial populations as well as symbiotic populations are of great interest in studies on deep-sea microbial ecosystems. Watsuji and colleagues investigated the epibiotic microbial communities of the deep-sea vent-endemic squat lobster  systems –22. In a animals . These f animals .Osedax japonicus, which thrives on fallen whole bones (Deep-sea virospheres have been attracting increasing interest. Viral abundance and diversity in various deep-sea waters and sediments have been intensively investigated using metagenomic analyses of viromes , 26. Howle bones . This vile bones . By applMicrobes and Environments. As the Editor-in-Chief and a deep-sea microbiologist, I hope that Microbes and Environments will become an attractive medium for a wide spectrum of research on deep-sea microbiology.Deep-sea microbiology has not been extensively reported in


Arboviruses are viruses transmitted to humans by the bite of infected mosquito vectors. Over the last decade, arbovirus circulation has increasingly been detected in New Caledonia (NC), a French island territory located in the subtropical Pacific region. Reliable epidemiological, entomological, virological and climate data have been collected in NC over the last decade. Here, we describe these data and how they inform arboviruses’ epidemiological profile. We pinpoint areas which remain to be investigated to fully understand the peculiar epidemiological profile of arbovirus circulation in NC. Further, we discuss the advantages of conducting studies on arboviruses dynamics in NC. Overall, we show that conclusions drawn from observations conducted in NC may inform epidemiological risk assessments elsewhere and may be vital to guide surveillance and response, both in New Caledonia and beyond. Aedes aegypti), the relatively low co-circulation of several arboviruses, the marked seasonality and the reliable epidemiological and entomological surveillance systems reduce this complexity, establishing NC as a simple and relevant ecosystem where these determinants and their interactions can be thoroughly analyzed. Here, we present the epidemiological, entomological, virological and climate data collected in NC over the last decade and how they inform arboviruses’ epidemiological profile. We also discuss the advantages of conducting studies on arboviruses dynamics in NC.In the past decade, arbovirus co-circulation has increasingly been detected in New Caledonia (NC), a French island territory located in the subtropical Pacific region with a population of approximately 280,000 A. In couhttps://dass.gouv.nc/votre-sante/documents-rapports-etudes). DENV-1 circulated uninterruptedly during those periods, co-circulating with DENV-4 in 2009, DENV-3 in 2014, DENV-2 and -3 in 2017 and DENV-2 in 2018 (https://dass.gouv.nc/votre-sante/documents-rapports-etudes). Molecular surveillance showed that DENV-1-genotype I replaced DENV-1-genotype IV in 2012 [https://dass.gouv.nc/votre-sante/documents-rapports-etudes) (https://dass.gouv.nc/votre-sante/documents-rapports-etudes)  is the major arbovirus circulating in the Pacific region . Over ea in 2018 B (https:-etudes) B. Despit-etudes) B. No sighttp://www.isee.nc/population/demographie/migrations) along with moderate fertility  are unlikely to lead to dramatic changes in population immunity, a protective population immunity threshold has probably not been reached, as outbreaks occurred in 2013–2014 and in 2016–2018.In NC, the percentage of the population protected against arboviruses is unknown. Population immunity shapes the epidemiological profile of arbovirus circulation. Introduction of an arbovirus in an immunologically naïve population favours outbreak occurrence. Unlike that of ZIKV, however, the introduction of CHIKV did not lead to major outbreaks. DENV-1 has been circulating continuously since 2008; as the low net migration  identified Ae. aegypti as the main vector for arboviruses in NC. The Larvae and Pupae Index (LPI) is a proxy for Ae. aegypti density and was calculated as the average number of late-instar larvae and pupae per house for 300 randomly selected houses visited per month. LPI remained low from 2010 to 2016 in Noumea (http://www.institutpasteur.nc/wp-content/uploads/2016/12/)  C but a dAe. aegypti from NC is competent for DENV, ZIKV and CHIKV. The Extrinsic Incubation Period, however, is three days for CHIKV [Could outbreaks be determined by the ability of available vectors to transmit the virus? Vector competence studies showed that or CHIKV , seven dor CHIKV  and nineor CHIKV . Furtheror CHIKV , <10% foor CHIKV  and 5% for CHIKV . Althoughttps://climatedataguide.ucar.edu/climate-data/cmap-cpc-merged-analysis-precipitation. Air temperature were taken from https://www.esrl.noaa.gov/psd/data/gridded/data.ncep.reanalysis2.html. The monthly data initially covering 1979–2018 were used to calculate a monthly seasonal cycle of surface precipitation and temperature and The climate of NC can be described as tropical A with a In a context of global climate change, seasonality in NC is expected to change in the region , resultiThe time of year at which the first arbovirus cases are detected on the territory is likely important. The risk of outbreak might be greater when an imported arbovirus is introduced during a favorable time of year.Interestingly, DENV and ZIKV are both flaviviruses and both caused outbreaks in NC. Neither CHIKV over the last decade nor Ross River Virus (RRV) in the late seventies —both alpGenotype, clade and strain replacements may impact DENV epidemiological profile by modulating viral replicative fitness . As DENVA better and more complete understanding of the peculiar epidemiological profile of arbovirus circulation in NC and its determinants can improve risk evaluation and public health planning before sizeable outbreaks. Although fragmented and incomplete, data collected over the last decade enabled a better description and understanding of this epidemiology. From these observations, we can conclude that predicting the occurrence of arbovirus outbreaks in NC relies on multiple factors. Measuring their interactions using mathematical models is of prime importance to identify new combinations of parameters to take into account when attempting to decipher the causes leading to an arbovirus outbreak. Modelling may help identify and understand the mechanisms that underlie the dynamics and evolution of arboviruses epidemiological profile in NC. Further, a deeper understanding of vector biology and population dynamics along with clinical and in vitro virological studies will generate highly informative data, to inform and strengthen these models. Finally, collecting more reliable data with higher spatial resolution on population immunity, vector densities, temperature/humidity oscillations, geolocalisation and time of cases’ introduction, genetic evolution and replicative fitness of the arbovirus introduced in its human and mosquito hosts will provide valuable input to build robust predictive models.New Caledonia is an island with limited and documented population exchanges and no sustained introduction of arboviruses cases. Its modest population size, effective surveillance, health and research systems, and the presence of only one known arbovirus vector make NC an ideal observatory of factors modulating the epidemiology of arboviruses and their differences. Wolbachia-treated Ae. aegypti will reshape the epidemiology of arbovirus circulation in NC. Understanding arbovirus epidemiology and its determinants before this implementation will provide a highly valuable baseline to document the effects of the Wolbachia strategy. Conclusions drawn from these observations may inform epidemiological risk assessments elsewhere—especially in non-endemic areas where the vector is present—and may be vital to guide surveillance and responses, both in New Caledonia and beyond. The World Mosquito Program will be implemented in Noumea in July 2019. The release of


Some studies showed that microRNA-497 (miR-497) might act as a prognostic biomarker of cancer. However, the conclusion was not consistent. The aim of this study was to investigate the prognostic role of miR-497 in various carcinomas.  We systematically searched the databases of PubMed, Embase, Web of Science, Chinese National Knowledge Infrastructure (CNKI), and Wanfang Data to identify relevant studies. Two independent reviewers performed the data extraction and assessed the study quality. Hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) for overall survival (OS) and disease-free survival/relapse-free survival (DFS/RFS) were used to assess the associations between miR-497 expression and cancer prognosis.  A total of 15 studies involving 1760 participants fulfilled the inclusion criteria. The lower level of miR-497 expression was significantly associated with shorter overall survival . No significant association was found between miR-497 expression and DFS/RFS in various carcinomas . Subgroup analyses by ethnicity and cancer type showed the consistent results.  Our studies suggested that miR-497 might be a prognostic biomarker in cancers. However, further multicenter prospective clinical researches are needed to confirm the association between miR-497 expression and cancer prognosis. MicroRNAs (miRNAs) are highly conserved, endogenous non-protein-encoded small molecules with lengths of 21 to 24 nucleotides which can bind to the target sequence of the 3′-untranslated region (3′-UTR) of the target mRNAs, causing degradation or translation inhibition of the target mRNAs at the posttranscriptional level , 6.MicroRNA-497 (miR-497) belongs to the miR-15 superfamily, sharing the same 3′-UTR binding seed sequence AGCAGCA . SubsequIn this systematic review and meta-analysis, we summarized available data from the published studies to evaluate the role of miR-497 as a prognostic biomarker and to clarify the association between miR-497 expression and long-term survival and early prediction in various carcinomas.We systematically searched the databases of PubMed, Embase, Web of Science, Chinese National Knowledge Infrastructure (CNKI), and Wanfang Data to identify relevant studies up to 15 October 2018. The following search strategies were used to retrieve articles in English or Chinese: “(miR497 OR miR-497 OR microRNA497 OR microRNA-497) AND (neoplasms OR cancer OR carcinoma) AND prognosis.” The reference lists of retrieved studies were also examined manually to identify potentially missing relevant studies.Inclusion criteria are as follows: (1) the full-text article written in English or Chinese, (2) the subjects were patients with any type of carcinoma, (3) miR-497 expression measured in tumor tissue, (4) evaluating the association between the miR-497 expression level and survival outcomes, including overall survival (OS), disease-free survival (DFS), and relapse-free survival (RFS), (5) reporting hazard ratio (HR) with 95% confidence interval (95% CI) or survival curves, and (6) studies based on the same population, with only the latest study included.Exclusion criteria are as follows: (1) reviews, letters, case reports, and conference reports and (2) lacking key information about survival outcomes.Two reviewers extracted data independently from eligible studies. The following information was extracted: the first author, publication year, country, ethnicity of patients, number of cases, cancer type, tumor stage, sample type, detection method, follow-up and cut-off values, HR, and the corresponding 95% CI of miR-497 for OS, DFS, and RFS. If obtaining directly is not possible, data were extracted by survival curves and calculated following Tierney et al.'s method . HR was Disagreements were resolved through comprehensive discussion and examined by a third investigator.The quality of each included study was assessed according to the Newcastle-Ottawa Scale (NOS) criteria for cohort studies . The NOSThe assessments were processed independently by two reviewers and the final score was achieved by consensus.Z-test, and P < 0.05 was regarded as statistically significant. Heterogeneity between studies was tested by the Q test and I2 statistics. If Pheterogeneity < 0.10 or I2 > 50% (heterogeneity existed), the random effects model was applied to calculate pooled HR and meta-regression was further used to explore sources of heterogeneity. If not, the fixed effects model was applied. The subgroup analyses were conducted by ethnicity and cancer type. Sensitivity analyses were performed by omitting each study at a time to assess the consistency and stability of the pooled results. We evaluated potential publication bias by funnel plots and further used Begg's test (rank correlation test) [Statistical analyses were performed using Review Manager 5.3  and Stata 14.0 , and all tests were 2 tailed. HRs and corresponding 95% CIs extracted directly or by survival curves were used to calculate the pooled HR by the generic inverse variance method. The significance of pooled HR was calculated by the on test)  and Eggeon test)  to quanton test)  was used324 studies were initially identified through database searching. 278 studies were further reviewed after duplicates were removed. According to the inclusion and exclusion criteria, 258 studies were excluded after screening titles and abstracts, 20 full-text articles were further assessed for eligibility. One retracted article , three aThe included studies encompassed a total of 1317 patients with OS data and 443 patients with DFS/RFS data from China, Ireland, and Austria, published from 2012 to 2017. The patients could be divided into Asian or Caucasian by their ethnic background. The types of carcinomas included hepatocellular carcinoma (HCC), cervical cancer, neuroblastoma, ovarian cancer, pancreatic cancer, osteosarcoma, breast cancer, gliomas, non-small-cell lung cancer (NSCLC), renal cancer, gastric cancer (GC), diffuse large B-cell lymphoma (DLBCL), colorectal cancer, and Ewing sarcoma. All studies used tissue specimens. Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted in all 15 studies. All of the follow-up time was more than 60 months. The cut-off values were different, most with median or mean. HR and the corresponding 95% CI were obtained directly in 8 studies, and others were extracted and calculated by survival curves.All studies included in this meta-analysis were cohort studies and assessed based on the NOS. The scores ranged from 6 to 8, and the average score was 7.13. The details of characteristics and the NOS scores were summarized in 15 studies evaluated the association of miR-497 expression levels and OS, and the pooled HR was 2.19 (95% CI: 1.84-2.60), which indicated that the lower level of miR-497 expression was associated with shorter overall survival . SubgrouData on DFS/RFS were available in 4 studies, and the pooled result showed no statistical association between miR-497 expression and early predicted survival  . SubgrouP > 0.05). It was indicated that the pooled results were not affected by above covariates , cancer type, NOS (mean 7.13 as the boundary), and cut-off. Univariate and multivariate analyses both showed that all the above covariates were not the sources of heterogeneity   .Results of this meta-analysis, for the first time, showed that the lower level of miR-497 expression was associated with shorter overall survival but not significantly associated with DFS/RFS in patients with a variety of carcinomas. Subgroup analyses by ethnicity and cancer type showed the consistent results. Sensitivity analyses which were performed by omitting each study at a time did not alter the results. Both analyses indicated that the results of this meta-analysis were stable and reliable.The main reason for the poor survival of cancer is invasion and metastasis . miR-497According to the NCI Dictionary of Cancer Terms, DFS and RFS are the same outcomes which are defined as “the length of time after primary treatment for a cancer ends that the patient survives without any signs or symptoms of that cancer.” Due to the included studies that used DFS or RFS to evaluate early tumor relapse, we combined the two indices to evaluate the early predictive value of miR-497. However, only 4 related studies with a relatively small sample size were included in this meta-analysis, so the result was less reliable to some extent. To confirm whether the miR-497 expression can predict the early tumor relapse or not, more well-designed clinical researches with larger sample sizes should be carried out in the future.Obvious heterogeneity was discovered when we conducted analysis of the miR-497 expression level and DFS/RFS. In order to find out the origin of heterogeneity, we performed the subgroup and sensitivity analyses. When we omitted the study of Zhang et al. , there wAlthough this meta-analysis suggested that miR-497 had clinical utility for the prediction of prognosis in patients with cancers, several issues should be considered about its clinical application. First, it is very important to determine a clear definition of the cut-off value of miR-497 expression. But the lack of abundant miR-497 expression data and the variability in different ethnic populations make it difficult to set a standard cut-off value. Second, several other miRNA prognostic biomarkers of cancers have been reported nowadays, such as miR-210 , miR-218This study has several limitations. First, the cut-off value of miR-497 expression was various in original studies, including median, mean, and others, lacking of a golden standard and a clear definition. Second, because survival data of some eligible studies could not be obtained directly by multivariate cox regression, the data extracted from survival curves might not exclude the influence of some potential confounding factors; these calculated HRs and corresponding 95% CIs might also bring several tiny errors. Third, heterogeneity between some studies still existed, although we used several statistical methods to minimize the effect of the heterogeneity, including the random effects model, subgroup analysis, and meta-regression.In conclusion, the current meta-analysis demonstrated that miR-497 expression was significantly associated with long-term survival, not significantly associated with early prediction. It might suggest that detected miR-497 expression could predict overall survival of cancer patients in the future clinical application. More multicenter prospective clinical researches should be conducted to confirm the association between miR-497 expression and cancer prognosis.


Congenital Zika virus (ZIKV) infection was first linked to birth defects during the American outbreak in 2015/2016. It has been proposed that mutations unique to the Asian/American-genotype explain, at least in part, the ability of Asian/American ZIKV to cause congenital Zika syndrome (CZS). Recent studies identified mutations in ZIKV infecting humans that arose coincident with the outbreak in French Polynesia and were stably maintained during subsequent spread to the Americas. Here we show that African ZIKV can infect and harm fetuses and that the S139N substitution that has been associated with the American outbreak is not essential for fetal harm. Our findings, in a vertical transmission mouse model, suggest that ZIKV will remain a threat to pregnant women for the foreseeable future, including in Africa, Southeast Asia, and the Americas. Additional research is needed to better understand the risks associated with ZIKV infection during pregnancy, both in areas where the virus is newly endemic and where it has been circulating for decades. th century. Along the way the virus diversified, so that now two genetic lineages, African and Asian/American, are recognized. Congenital Zika syndrome (CZS), the set of fetal and neonatal complications associated with ZIKV infection in pregnancy, was noted during the recent outbreak in the Americas. But the origins of CZS remain a mystery. In particular, it is unclear whether ZIKV recently acquired the ability to cause CZS, perhaps as Asian-lineage viruses spread to the Americas, or whether African-lineage viruses can also cause CZS. To address this question, we used a mouse model of vertical ZIKV transmission to assess pathogenic potential to the fetus of African and Asian/American ZIKV. Our data show that ZIKV of both African and Asian/American lineages can cause fetal harm in the mouse pregnancy model, and that this capacity does not require asparagine at amino acid residue 139, which recently emerged in Asian-lineage viruses and has been suggested to increase ZIKV’s pathogenic potential for fetuses. Our results, therefore imply that ZIKV infection during pregnancy poses a risk for fetal harm in all regions where the virus is endemic.Zika virus (ZIKV) was first discovered in Uganda in 1947, and is thought to have spread from Africa through equatorial Asia in the middle of the 20 Zika virus causes adverse pregnancy outcomes including fetal loss, developmental abnormalities, and neurological damage, collectively termed congenital Zika syndrome (CZS) –4. Why din vitro) and mouse (in vivo) neural progenitor cells (NPCs), leading to restricted brain growth in an ex vivo embryonic mouse brain model, as well as higher mortality rates in neonatal mice following intracranial (i.c.) inoculation. Zhang et al. . At. At16].  fetuses . Only fep-value < 0.0001, t-value = 5.04, df = 95; p-value = 0.063, df = 47; ZIKV-PR-IC vs. ZIKV-DAK: p-value = 0.43, df = 47; ZIKV-PR-N139S vs. ZIKV-DAK: p-value = 0.64, df = 47; one-way ANOVA with Tukey’s multiple comparisons). In contrast, ZIKV-DAK infected fetuses had significantly higher viral loads when compared to ZIKV-PR-IC and ZIKV-PR-N139S . Although day 2 viremia was significantly higher in ZIKV-DAK-infected dams, the fact that fetal and placental viral loads are broadly similar, both within and across treatment groups indicates that it is not simply a matter of enhanced replication of the African virus in the dam causing more severe fetal outcomes. Still, we cannot exclude the possibility that the more severe fetal outcomes observed with the African virus are the result of IFNAR-dependent fetal demise [in utero exposure may not be evident at birth [To confirm vertical transmission of ZIKV to the developing conceptus, viral loads were measured from representative placentas and fetuses from each litter of all treatment groups by quantitative RT-PCR . vRNA wal demise  singly oat birth .in utero ZIKV infection, tissues of the developing placenta and decidua were evaluated microscopically. In PBS-inoculated dams, we observed normal decidua, junctional zone, and labyrinth with normal maternal and fetal blood spaces (To better understand the impact of d spaces . In contd spaces . There ad spaces . These dImportantly, we assessed outcomes following only a single infection time point at E7.5 and outcomes may differ depending on the timing of infection. Critically, the placenta acts as a barrier against infections but does not have a definitive structure in mice until the midpoint of gestation: ~E10.5–11.5 . It is pTogether our data show that infection with ZIKV isolates of either the African or Asian lineages during pregnancy can lead to fetal harm, with varying levels of damage to maternal, placental, and fetal tissues, frequently including death of the developing fetus. Likewise, intracranial inoculation of neonatal mice confirmed a similar neurovirulence phenotype across ZIKV lineages. A recent study identified the potential capacity of an ancestral Asian strain to cause fetal brain infection after maternal infection in mice ; that st


Background: External auditory stimuli have been widely used for recovering arm function post-stroke. Rhythmic and real-time auditory stimuli have been reported to enhance motor recovery by facilitating perceptuomotor representation, cross-modal processing, and neural plasticity. However, a consensus as to their influence for recovering arm function post-stroke is still warranted because of high variability noted in research methods.Objective: A systematic review and meta-analysis was carried out to analyze the effects of rhythmic and real-time auditory stimuli on arm recovery post stroke.Method: Systematic identification of published literature was performed according to PRISMA guidelines, from inception until December 2017, on online databases: Web of science, PEDro, EBSCO, MEDLINE, Cochrane, EMBASE, and PROQUEST. Studies were critically appraised using PEDro scale.Results: Of 1,889 records, 23 studies which involved 585  patients met our inclusion criteria. The meta-analysis revealed beneficial effects of training with both types of auditory inputs for Fugl-Meyer assessment (Hedge's g: 0.79), Stroke impact scale (0.95), elbow range of motion (0.37), and reduction in wolf motor function time test (−0.55). Upon further comparison, a beneficial effect of real-time auditory feedback was found over rhythmic auditory cueing for Fugl-meyer assessment (1.3 as compared to 0.6). Moreover, the findings suggest a training dosage of 30 min to 1 h for at least 3–5 sessions per week with either of the auditory stimuli.Conclusion: This review suggests the application of external auditory stimuli for recovering arm functioning post-stroke. According to World health organization, stroke accounts as the third main cause of disability across the world . The incTypically, patients affected from stroke exhibit sensorimotor dysfunctions on the contralateral side of the affected brain region . These dThe poor gross and fine motor performance in upper extremities can be due to abnormal co-contraction of antagonists/agonists , disruptNeuroimaging studies suggest site specific lesions and silent infarcts at medial temporal lobe , gray 3, and whiCommon treatment strategies to curb cognitive motor dysfunctions in stroke patients include training with virtual-reality , mental In the literature, however, rhythmic auditory cueing , and reaTill date, no study has analyzed the influence of real-time auditory feedback on upper limb recovery post-stroke. Moreover, no study has compared the influence of rhythmic and real-time auditory stimuli on upper limb recovery post stroke. This information might serve to be an important source of information for future research and for developing efficient rehabilitation protocols in stroke community. Only four systematic reviews have analyzed the influence of rhythmic auditory stimulations on arm recovery post stroke , 101–103This systematic review and meta-analysis was conducted according to the guidelines outlined by PRISMA statement: Preferred Reporting Items for Systematic Reviews and Meta-analysis .Academic databases: Web of science, PEDro, EBSCO, MEDLINE, Cochrane central register of controlled trials, EMBASE, and PROQUEST were searched from inception until December 2017. A sample search PICOS strategy for the review has been provided in Table .Upon selection for review, the following data were extracted from each article; author, date of publication, selection criteria, sample size, sample description , applied intervention, characteristics of auditory stimuli i.e., rhythmic/real-time, applied dual-task (if any), outcome measures, results, and conclusions. The data were then summarized and tabulated Table .The inclusion criteria for the studies was (i) The experimental studies were either randomized controlled trials, cluster randomized controlled trials or controlled clinical trials; (ii) The included studies reported reliable and valid measures to analyse arm function, and/or kinematic parameters; (iii) The included studies analyzed subjective analysis of stroke outcome; (iv) The included studies scored ≥4 score on the PEDro methodological quality scale; (v) The experiments conducted on human participants; (vi) The included studies were published in a peer-reviewed academic journal, conference proceeding; (vii) The included studies were published in English, Hindi, Punjabi, and German languages.The quality of the included experimental studies was assessed using the PEDro methodological quality scale . This sc2 statistics. The data in this present review was systematically distributed and pooled for each variable. Thereafter, forest plots with effect size and 95% confidence intervals were plotted. The effect sizes were weighted and reported as Hedge's g  of the participants were tabulated across the studies. Disease duration of stroke patients has also been mentioned for better interpretation of the reader. However, five studies did not mention these details , 125.Studies scoring ≥4 on PEDro methodological scale were included in the review. Individual scores have been reported Table . The aveThe results clearly suggest a positive influence of training with rhythmic auditory cueing and real-time auditory feedback on arm recovery post-stroke. Out of 23 included studies, significant enhancement was reported in 19 studies, three studies reported enhancements, and only one study reported significant reduction in arm function post training with auditory stimuli  and moderate heterogeneity was observed in between the studies . Further, on separating the studies for comparing the effects of rhythmic auditory cueing and real-time auditory feedback, nine studies were analyzed for their effects on rhythmic auditory cueing and three studies for real-time auditory feedback.Fugl Meyer assessment scores for arm performance were assessed in 11 studies. Here, two studies evaluated the score on stroke patients while using real-time auditory feedback, whereas nine studies utilized rhythmic auditory cueing. The analysis of studies revealed Figure  a large medium effect size with negligible heterogeneity . An analysis for effects of real-time auditory feedback on Fugl Meyer assessment revealed .An analysis for effects of rhythmic auditory cueing on Fugl Meyer assessment revealed . Only one study  for rhythmic auditory cueing revealed . Further, an analysis for only rhythmic auditory cueing revealed .An analysis for effects of rhythmic and real-time auditory stimuli on Wolf motor time assessment revealed Figure  a negatimedium effect size with negligible heterogeneity .A further sub-group analysis based on the amount of training dosage  for rhythmic auditory cueing revealed . Further, a sub-group analysis for only rhythmic auditory cueing revealed a similar positive medium effect size with negligible heterogeneity . Further sub-group analysis was not performed because two studies did not include a training regime . Further, a sub-group analysis for only real-time auditory feedback training  revealed a similar positive large effect size with substantial heterogeneity . Here, heterogeneity could be affirmed to considerable differences in the characteristics of real-time auditory feedback provided to the patients .Analysis for effects of rhythmic and real-time auditory stimuli on Nine-hole peg test revealed . Here, heterogeneity could be affirmed to considerable differences in the characteristics of rhythmic auditory cueing provided to the patients  revealed a similar positive large effect size with substantial heterogeneity . Further, a sub-group analysis for only rhythmic auditory cueing  revealed a similar positive large effect size with substantial heterogeneity . Here, substantial amount of heterogeneity could be due to considerable differences in the characteristics of real-time auditory feedback provided to the patients , concerns regarding biasing, methodological flaws in the study's design and outcomes could be expected . Here, tIn conclusion, this present review for the first time analyzed the effects of rhythmic and real time auditory stimuli on arm recovery in post-stroke patients. The present findings are in agreement with systematic reviews and meta-analysis carried out to analyze auditory entrainment effect on aging , cerebraSG conceptualized the study, carried out the systematic review, statistical analysis, and wrote the paper.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Repetitive head trauma provides a favorable milieu for the onset of inflammatory and neurodegenerative processes. The result of long-lasting head trauma is chronic traumatic encephalopathy (CTE), a disease process well-recognized in boxers, military personnel, and more recently, in American football players. CTE is a chronic neurodegenerative disease with hallmarks of hyperphosphorylated tau (p-tau) aggregates and intercellular lesions of neurofibrillary tangles. The criteria for CTE diagnosis requires at least 1–2 focal perivascular lesions of p-tau in the cerebral cortex, at the depth of the sulci. These pathognomonic lesions aggregate within neurons and glial cells such as astrocytes, and cell processes within the vicinity of small blood vessels. CTE presents in a distinct topographical distribution pattern compared to other tauopathies such as AD and other age-related astrogliopathies. CTE also has an insidious onset, years after repetitive head trauma. The disease course of CTE is characterized by cognitive dysfunction, behavioral changes, and can progress to altered motor function with parkinsonian-like manifestations in later stages. This short review aims to summarize CTE in professional football, epidemiology, diagnosis based on neuroanatomical abnormalities, cognitive degeneration, and adverse mental health effects, as well as gaps in the literature and future directions in diagnostics, therapeutics, and preventive measures. Individp = 0.03 (left hemisphere), p = 0.03 (right hemisphere)]. Additionally, younger AFE has also been related to reduced left thalamic volume (p = 0.014)  to contact football has also been associated with neurological and psychiatric dysfunction in later life , 34, 44.= 0.014) , and altQuantifying the epidemiology of CTE requires further elucidation, as studies have largely involved cohorts with a history of repetitive brain trauma such as athletes . This has led to an overestimation of prevalence  due to tA history of brain trauma also appears to be an antecedent for the onset of CTE. In a sample of 1721 cases of contact sport athletes,  reportedAlthough emerging evidence has highlighted the use of 2-(1-{6-[(2-[F-18] fluoroethyl) (methyl)amino]-2-naphthyl}ethylidene) malononitrile-positron emission tomography ([F-18] FDDNP PET) and other neuroimaging techniques for a preliminary pre-mortem diagnosis , 54, a dThe classical signs of CTE induced macroscopic changes are more commonly found in advanced forms of CTE, and rarely manifest in early stages . They inSD = 12.7) after initial exposure, but ranges from 25 to 76 years of age , motor neuron disease such as Amyotrophic Lateral Sclerosis , 68 and Despite prevailing media reports of several ex-NFL players taking their own lives, and post-mortem showing hallmark traits of CTE, no causal link exists between CTE and suicide . Previouin-vivo. In professional football players, [F-18] FDDNP PET has been shown to be an archetypal tau ligand, as the imaging pattern seen presents in a characteristic topographical distribution consistent with that of CTE . The safety profile and consideration of magnetic resonance spectroscopy (MRS) as a “virtual biopsy” are conducive to inclusion in the emerging search for tools to diagnose CTE . Neuromeecessary , 82.Recently, the field has also advanced in identifying potential biomarkers of traumatic brain injury. There are a range of biomarkers approaching clinical validation  and more emerging, such as microtubule associated protein-2 (MAP-2) and brain-derived neurotrophic factor (BDNF) , 84. In Recent work has shed light into the molecular etiopathogenesis of CTE, specifically the inflammatory cascade that results in hyperphosphorylated p-tau accumulation. A seminal paper by Lucke-Wold et al. , has shohttps://www.playsmartplaysafe.com/) highlights the leagues updated concussion protocols and return-to-play guidelines; the NFL works to ensure concussed players adhere strictly to these return-to-play guidelines after brain trauma. This is in an effort to prevent exacerbation of injury, or occurrence of a second episode (What is most concerning about NFL-associated CTE cases is their preventable nature. There is a preponderance of ex-NFL players that allege the NFL failed to provide information regarding the neuropsychiatric risks associated with playing professional football , 90. Rec episode . Non-com episode . The res episode . Athletein-vivo diagnostic techniques such as MRI and [F-18] FDDNP PET being explored, and therapeutic modalities showing promise in murine models. However more clinical human studies are warranted for timely diagnosis and appropriate management of CTE.Our understanding of CTE in American football players has improved immensely since the first case reports of Omalu and colleagues. It has now emerged that CTE has afflicted football players from bouts of head trauma. Despite these advances, more work is necessary to elucidate the underlying pathophysiological mechanisms, and the incidence and prevalence of disease burden in the general populace. There is a need to move beyond case reports and focus on more systematic studies examining CTE in sport and non-sport populations. At present, there is also no widely accepted clinical criteria for a diagnosis of CTE despite the preliminary work of McKee et al.  and othein vivo potential diagnostics section. TCT assisted in manuscript drafting and wrote the future directions section. TAT critically edited the manuscript for intellectual content, and provided guidance. All authors edited and approved the final version of the manuscript, and agree to be accountable for all aspects of this work. The authors have no conflicts of interests to declare.TT was responsible for conception of the mini-review, manuscript drafting, submission, and was involved in all aspects of this paper. MI assisted in manuscript preparation and wrote pathological findings section. IT provided advice and guidance during the completion of the manuscript and assisted in submission process. PG-R wrote the future directions in 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.


Mapping individual brain networks has drawn significant research interest in recent years. Most individual brain networks developed to date have been based on fMRI or diffusion MRI. Given recent concerns regarding confounding artifacts, various preprocessing steps are generally included in functional or structural brain networks. Notably, voxel-based morphometry (VBM) derived from anatomical MRI exhibits high signal-to-noise ratios and has been applied to individual interregional morphological networks. To the best of our knowledge, individual voxel-wise morphological networks remain unexplored. The goal of this research is twofold: to build novel metrics for individual voxel-wise morphological networks and to test the reliability of the proposed morphological connectivity. To this end, anatomical scans of a cohort of healthy subjects were obtained from a public database. The anatomical datasets were preprocessed and normalized to the standard brain space. For each individual, wavelet-transform was applied on the VBM measures to obtain voxel-wise hierarchical features. The voxel-wise morphological connectivity was computed based on the wavelet features. Reliable brain hubs were detected by the z-scores of degree centrality. High reliability was discovered by test-retest analysis. No effects of wavelet scale, network threshold or network type were found on hubs of group-level degree centrality. However, significant effects of wavelet scale, network threshold and network type were found on individual-level degree centrality. Significant effects of network threshold and network type were found on reliability of degree centrality. The results suggested that the voxel-wise morphological connectivity was reliable and exhibited a hub structure. Moreover, the voxel-wise morphological connectivity could reflect individual differences. In summary, individual voxel-wise wavelet-based features can probe morphological connectivity and may be beneficial for investigating the brain morphological connectomes. Voxel-based morphometry (VBM) is a neuroimaging tool that can probe local differences of brain anatomy and has been applied in statistical analysis , 2 and dMapping individual morphological relationships is a challenging task based on local features of an anatomical volume. Interregional image density distribution-based Kullback-Leibler (KL) divergence has been recently applied to measure individual morphological connectivity . The intMapping inter-voxel morphological relationships at the single-subject level remains largely underexplored, as there is a lack of local features in a single voxel of an anatomical volume. Notably, voxel patch-based similarity has been applied to extract individual brain networks from structural MRI scans , which hWavelet transform has been applied in brain morphometry studies . The wavIn this paper, we aimed to map the individual voxel-wise morphological connectivity based on anatomical MRI and to test the reliability and variability of the voxel-wise morphological connectivity. To this end, a cohort of adult participants was obtained from a publicly available MRI database. The method section describes the application of the wavelet transform to the VBM data to obtain multi-resolution features for a single volume. Wavelet-based similarity was applied as the voxel-wise morphological connectivity. In the result section, the reliability and variability of the voxel-wise morphological connectivity were evaluated using statistical analysis. In the discussion section, we summarize the reliability and variability of the voxel-wise morphological networks.https://www.nitrc.org/projects/multimodal/).Twenty-one healthy subjects  without neurological history were recruited at Vanderbilt University, USA . For eacThe structural MRI datasets were first reoriented to the standard space, automatic cropped, bias field corrected, and skull-stripped to exclude non-brain tissues. The brain images were then segmented into gray matter, white matter, and cerebrospinal fluid. Third, the original and segmented images were spatially normalized to the standard brain space. Fourth, the spatial normalized gray matter image was multiplied by the Jacobian of the warp field. Finally, the modulated gray matter image was obtained as the VBM features. The spatial normalization procedure was carried out using the fsl_anat command. The VBM procedure was carried out using the fslvbm command.The wavelet transform was applied to extract local and global features for the VBM volumes, resulting in hierarchical features for each single voxel. Thus, the wavelet transform could provide richer information than the conventional VBM method. A wavelet can be defined as a small wave-like oscillation that can be used to decompose a time-domain or spatial-domain signal into different scales . The wavThe nodes and edges of brain networks should be defined before computing voxel-wise morphological relationships. The locations of nodes were defined using the first 90 brain regions in the automated anatomical labeling (AAL) atlas, resulting in 159841 nodes in the 2 mm×2 mm×2 mm 3D space. Given a voxel-wise morphological network, the morphological connectivity (edge) between two voxels (nodes) can be defined by the Pearson correlation coefficient of pairwise wavelet feature vectors in brain voxels.Here, w denotes the wavelet feature vector within a voxel, cov denotes covariance, and δ denotes the standard deviation of the wavelet feature vector. For a wavelet scale of n, the length of the wavelet feature vector is 2*n.For a binarized graph, the links are defined as:For a weighted graph, the links are defined as:r0 denotes the threshold for a graph [r0 for morphological connectivity were set to 0.5, 0.6, 0.7, 0.8 and 0.9 for sparsity.Here, i and j denote the two voxels, and  a graph . The thrhttps://www.nitrc.org/projects/mcwt/).Given a wavelet-transformed 4D VBM volume for each individual, voxel-wise morphological relationships were computed by the following steps: 1) The voxel-wise wavelet features are obtained; 2) The voxel-wise features are masked using the AAL atlas; 3) the Pearson correlation coefficients of pairwise wavelet features between the two voxels are derived; 4) The voxel-wise morphological connectivity is obtained; 5) Thresholds  are applied to the voxel-wise morphological connectivity; 6) The voxel-wise nodal degree of morphological connectivity is obtained. The pipeline to obtain individual voxel-wise morphological connectivity is illustrated in Centralities are the most common graph measures for nodal estimators  , 20–22. Both binarized and weighted graphs were analyzed through thresholding the symmetrical matrix of morphological connectivity . Degree iD indicates the ith voxel-wise degree centrality, D indicates the whole-brain voxel-wise degree centrality, and std indicates the standard deviation.Hub voxels contain more connections than other voxels within a voxel-wise network. To detect the hubs of the voxel-wise networks, the raw scores of degree centrality were first transformed into z-scores. Then, group-level z-scores of degree centrality were obtained by averaging the individual degree centrality with different effects . Finally, for each effect factor, the hub voxels were indicated by those with a z-score >1, according to previous studies –26.A test-retest analysis was applied to investigate the reliability of the proposed voxel-wise morphological network. The test-retest reliability was analyzed via the intraclass correlation coefficients (ICCs) , 28. In To analyze the effects of wavelet scale , network threshold , and network type  on the network hubs and network reliability, three-way Analysis of Variance (ANOVA) was performed on the group-level degree centrality or reliability maps using the following formula:Here, Y denotes group-level degree centrality or reliability maps, and A, B, and C denote wavelet scales, network thresholds, and network types, respectively.To analyze the effects of wavelet scale, network threshold, and network type on individual differences in degree centrality, repeated-measures ANOVA was performed on the individual-level degree centrality maps using the following formula:Here, DC denotes the individual-level degree centrality, and A, B, and C denote wavelet scales, network thresholds, and network types, respectively. The results were corrected by the false discovery rate (FDR).The repeated-measures ANOVA analysis revealed significant  main effects and interaction effects of the three different factors  on individual-level degree centrality. A significant main effect of network threshold was found in 91.62% of the whole-brain voxels. A significant main effect of wavelet scale was found in 97.16% of the whole-brain voxels. A significant main effect of network type was found in 81.84% of the whole-brain voxels. A significant threshold:scale interaction was found in 99.1% of the whole-brain voxels. A significant threshold:type interaction was found in 88.24% of the whole-brain voxels. A significant scale:type interaction was found in 96.12% of the whole brain voxels. A significant threshold:scale:type interaction was found in 98.55% of the whole-brain voxels.In this study, we sought to map voxel-wise morphological connectivity at the single-subject level based on anatomical MRI. To this end, wavelet transform was applied on the VBM features. The morphological connectivity was obtained via the inter-voxel hierarchical wavelet features. The voxel-wise morphological networks exhibited good test-retest reliability across different wavelet scales, different network thresholds, and different network types. In addition, the voxel-wise morphological networks exhibited hub structures, most of which were located in the default mode network (DMN) area. Overall, the inter-voxel morphological relationships were successfully obtained for individuals through wavelet transform. The voxel-wise morphological connectivity might provide additional measures for studies of the human connectome.Wavelet transform can capture the local and global features of individual MRI datasets in a multi-resolution manner. Thus, individual brain networks can be built through wavelet-based hierarchical features in a straightforward manner. Wavelet transform has been employed as an efficient tool for feature extraction and signal representation . The comThe hub regions, which are connected to more brain nodes than other regions, may reflect the functional or structural cores within the brain networks. In this study, we found certain brain regions that exhibited hub organization , most of which were located in the DMN area. DMN-related morphological hubs might reflect structural or functional connections. Pervious evidence has indicated structural cores located in brain regions of the posterior components of the DMN . High glThe test-retest reliability is a key feature for evaluating novel neural metrics . The actIndividual differences are a fundamental property of a novel neural metric. Previous individual connectivity was based on diffusion MRI or functional MRI, which are both sensitive to confounding artifacts . Given tThis study is characterized by several advantages. First, the voxel-wise morphological network was investigated for single subjects in a wavelet-based framework. Evaluating the voxel-wise morphological connectivity for single subjects might be beneficial for investigating individual differences. Second, the wavelet transform could yield hierarchical features . Thus, the wavelet-based morphological connectivity could capture multi-resolution information. Third, the voxel-wise morphological connectivity detected reliable hub structures. The reliable hub structures identified by the framework might reflect the functional or structural basis of voxel-wise morphological connectivity. Fourth, the voxel-wise morphological estimators exhibited good test-retest reliability. Reliability is an essential feature for novel neural metrics. The reliable voxel-wise morphological estimators implied their potential values in clinical applications. In summary, the proposed morphological connectivity method was reliable across different network levels and could advance the study of individual variability.One limitation of this study is that the biological meanings of the proposed voxel-wise morphological connectivity feature could not be elucidated. Although reliable voxel-wise morphological connectivity was discovered by wavelet-based features, supplemental experiments are still required to test the hypothesis that morphological connectivity can reflect structural and functional connectivity. Moreover, there are numerous similarity and dissimilarity metrics  that can be applied to measure the morphological connectivity in additional studies. Another limitation of this study is the lack of physiological signals for references. The morphological similarity-based results could be interpreted with supplementary physiological measures , magnetoencephalography (MEG)) in future studies. The third limitation of this study is the relatively small sample size of participants. The results should be verified using different scanners and different populations in subsequent studies. Together, there are still many challenges that must be overcome in the study of voxel-wise morphological networks. Additional physiological measures might help interpret the novel individual morphological networks.This paper proposed a voxel-wise wavelet-based similarity measure to evaluate morphological connectivity at the single-subject level based on structural MRI. The morphological networks were reliable across different wavelet scales, network thresholds, and network types. The voxel-wise morphological connectivity exhibited excellent reliability and reflected individual differences. In summary, the voxel-wise wavelet-based similarity could probe individual morphological connectivity and could be beneficial for investigating the brain morphological connectome.