Many nematodes show context-dependent, experience-dependent and/or life-stage-dependent behavioural responses to CO2, suggesting that CO2 plays crucial roles throughout the nematode life cycle in multiple ethological contexts. Nematodes also show a wide range of physiological responses to CO2. Here, we review the diverse responses of parasitic and free-living nematodes to CO2. We also discuss the molecular, cellular and neural circuit mechanisms that mediate CO2 detection in nematodes, and that drive context-dependent and experience-dependent responses of nematodes to CO2.Carbon dioxide (CO The initial repulsion from CO2 experienced by Heligmosomoides polygyrus iL3s on feces may enable them to disperse off of feces and into the environment to host seek. Following a prolonged period without feces, CO2 attraction may drive them towards new hosts or fresh host feces to increase their chances of host entry through ingestion  in passively ingested ruminant parasites such as Haemonchus contortus  are parasites that infect and kill insects , suggesting that jumping is highly sensitive to environmental CO2  in Steinernema scapterisci is in fact regulated by ambient CO2 levels.Like some mammalian-parasitic nematodes, some EPNs exhibit plasticity in their olfactory responses to COof weeks   are a major cause of agricultural crop damage throughout the world. It has been estimated that PPNs are responsible for approximately 100 billion dollars of crop loss per year worldwide  are repelled by CO2. CO2 repulsion by JIVs plays an important role in dispersal from its insect vector, the pine sawyer beetle, into the pine tree  levels, as well as immediate O2 context. For example, animals exposed to elevated CO2 levels (2.5% CO2) become robustly attracted to CO2 over the course of hours in a reversible manner  inhibits egg-laying behaviour, at least transiently  mutations in npr-1 and animals carrying the natural variant of npr-1 avoid CO2 under low O2 conditions but do not respond to CO2 at normal atmospheric O2 levels (21% O2)  mutation or a natural variant of npr-1, the URX neurons are tonically active under high O2 conditions and inhibit CO2 avoidance at high O2. The RIA interneurons appear to act downstream of URX to partially mediate its effects on the CO2 circuit (Kodama-Namba et al., glb-5 also acts via the URX neurons to modulate CO2 responsiveness as a function of ambient O2 levels (McGrath et al., et al., The extent to which CO2 responsiveness in C. elegans have been elucidated in some detail. The shift in CO2 response from repulsion to attraction when animals are moved from low CO2 to high CO2 cultivation conditions results from the differential activity of a single set of interneurons downstream of the BAG sensory neurons (Guillermin et al., 2, CO2 exposure inhibits the AIY interneurons and activates the RIA and RIG interneurons. In contrast, in animals that have been cultivated at high CO2, CO2 exposure activates AIY and inhibits RIA. Moreover, RIG is silenced such that it no longer responds to CO2 (2 response is not determined by whether an ‘attractive’ or ‘repulsive’ pathway is activated; rather, it is determined by experience-dependent modulation of interneuron activity in a single pathway (Guillermin et al., 2 responsiveness in animals cultured under high vs low CO2 conditions (et al., The mechanisms underlying experience-dependent modulation of COs to CO2 . Thus, Cnditions  (Guiller et al., .2 repulsion to CO2 attraction that occurs during starvation also arises due to the differential activities of the AIY and RIG interneurons (Rengarajan et al., 2 evokes activating and inhibiting responses with approximately equal frequency (2 is attractive or repulsive is regulated by biogenic amine signalling. Dopamine promotes CO2 avoidance in well-fed animals by promoting activation of RIG and inhibition of AIY, while octopamine promotes CO2 attraction in starved animals by promoting activation of AIY (et al., 2 circuit is modulated during starvation by opposing biogenic amine signals. Neuropeptide signalling also regulates CO2 responsiveness during starvation (et al., 2 attraction in dauer larvae is less well understood but is regulated at least in part by neuropeptide signalling (Lee et al., The shift from COrequency . At the n of AIY  (Rengara et al., . Thus, tarvation  (Rengara et al., . Finally2 on other behaviours in C. elegans have also been elucidated. For instance, CO2-evoked activity in the AWC sensory neurons triggers a cGMP signalling pathway that ultimately inhibits the activity of the HSN neurons, resulting in the inhibition of egg-laying behaviour (Fenk and de Bono, C. elegans, resulting in increased longevity in BAG-ablated animals (Liu and Cai, jnk-1 and kgb-2 suppress CO2-induced fertility defects, indicating that JNK signalling may be involved in regulating fertility in response to CO2 (Vadasz et al., Some of the molecular and cellular mechanisms that mediate the effects of CO2 responsiveness in C. elegans have been elucidated in appreciable detail, several questions remain unexplored. For example, more information is needed to fully understand how the differential flow of information from BAG neurons to downstream interneurons generates experience-dependent plasticity of CO2-evoked behaviour. One intriguing possibility is that the BAG neurons express or release different neurotransmitters or neuropeptides in response to CO2 under varying conditions. Consistent with this possibility, the BAG neurons modulate the expression of FLP-19 neuropeptides as a function of their CO2-evoked activity (Rojo Romanos et al., 2-sensing neurons have not been identified. Finally, the CO2 microcircuit that drives CO2 attraction in dauers remains poorly understood, although it appears to involve dauer-specific, gap-junction-mediated signalling between the BAG neurons and the downstream AIB interneurons (Bhattacharya et al., 2 attraction in dauers. A better understanding of the neural circuits and signalling pathways that regulate CO2 responsiveness as a function of experience, context and life stage will provide important insights into how a single sensory cue can give rise to diverse behavioural responses in an ethologically-appropriate manner.Although the mechanisms underlying COet al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., 2 responsiveness in C. elegans as a starting point for launching investigations into the mechanisms of CO2 responsiveness in parasitic nematodes. In the case of both the necromenic nematode Pristionchus pacificus and the EPNs Heterorhabditis bacteriophora and Steinernema carpocapsae, BAG neurons were identified on the basis of conserved neuroanatomical position and shown to be required for behavioural responses to CO2 by laser ablation analyses (Hallem and Sternberg, et al., Pristionchus pacificus adults do not show acute CO2 avoidance, and BAG-ablated Heterorhabditis bacteriophora and Steinernema carpocapsae IJs do not show CO2 attraction (Hallem et al., 2-evoked jumping behaviour in Steinernema carpocapsae requires the BAG neurons (Hallem et al., 2 response are at least partly conserved across nematode species. However, the interneurons that operate downstream of BAG neurons to mediate CO2 responsiveness in other nematode species have not yet been identified. Moreover, nothing is currently known about the neural circuits and molecular signals that promote CO2 responsiveness in mammalian-parasitic nematodes. In future studies, it will also be interesting to determine whether similar or distinct mechanisms operate in C. elegans and parasitic nematodes to modulate CO2 responses depending on context, previous experience or life stage.The anatomy and function of nematode sensory neurons are generally conserved across species (Ashton 2 responsiveness in mammalian-parasitic nematodes. The identification of the neural mechanisms that drive or regulate the CO2 responses of mammalian-parasitic nematodes both inside and outside the host could lead to the identification of new drug targets or new strategies for nematode control. Until recently, investigations into the mechanisms underlying sensory behaviours in parasitic nematodes were limited to laser ablation analysis due to the dearth of resources and tools required for the genetic manipulation of these parasites. Laser ablation analysis has been used to establish the function of a number of different sensory neurons in mammalian-parasitic nematodes, including Strongyloides stercoralis, hookworms and Haemonchus contortus (Ashton et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., A major focus going forward will be on elucidating the cellular and molecular mechanisms underlying COStrongyloides stercoralis and Strongyloides ratti. Strongyloides stercoralis and Strongyloides ratti are more readily amenable to genetic manipulation than other parasitic nematodes because they can undergo one free-living generation (Viney, C. elegans (Evans, Strongyloides stercoralis is a human parasite that infects approximately 370 million people worldwide (Page et al., Strongyloides stercoralis is of interest as a model for other human-parasitic nematodes such as hookworms that cannot be genetically manipulated.The most genetically tractable parasitic nematodes are n Viney, . Foreigns Evans, . Most ot1 progeny of the microinjected adults (Lok and Massey, et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Strongyloides has been aided by the identification of several promoters that drive expression in single cells or subsets of cells (Junio et al., et al., et al., C. elegans are stably expressed across generations, extrachromosomal arrays in Strongyloides are silenced after the F1 generation by as-yet-unknown mechanisms (Junio et al., et al., Strongyloides by methods that promote genomic integration of transgenes, such as transposon-mediated random integration (Shao et al., et al., Transgenic nematodes can be generated by introducing plasmid DNA containing exogenous genes; these genes are then expressed as extrachromosomal arrays in the FStrongyloides stercoralis and Strongyloides ratti. The recent development of an approach for CRISPR/Cas9-mediated targeted gene disruption in these species provided the first insights into the genetic mechanisms that drive sensory behaviours (et al., et al., et al., Strongyloides stercoralis infective larvae (Bryant et al., Strongyloides ratti. RNAi approaches using both dsRNA and siRNA have been used to study the effects of transcriptional knockdown of genes in several parasitic nematode species, although with varying efficacy (Geldhof et al., et al., et al., et al., et al., et al., Strongyloides ratti, a recent study demonstrated the first successful knockdown of multiple mRNAs using an siRNA approach (Dulovic and Streit, Strongyloides ratti iL3s, although mapping the locations of these mutations has not been possible yet (Viney et al., et al., Methods for disrupting gene function are also now available for haviours  (Gang etStrongyloides stercoralis to CO2. For example, it will be interesting to determine whether the BAG neurons, which sense CO2 and promote behavioural responses to CO2 in C. elegans, play a similar role in Strongyloides stercoralis. It will also be important to elucidate the neural circuitry that operates downstream of the CO2-sensing neurons to mediate or modulate CO2-evoked behaviours in Strongyloides stercoralis. An intriguing possibility is that while sensory neuron function may be generally conserved across species, interneuron function may be less well conserved and may instead reflect species-specific behavioural and physiological responses to CO2. In addition, through the systematic screening of candidate genes known to be involved in CO2 responsiveness in C. elegans, it might be possible to uncover molecular signals that regulate parasite–host interactions or that are required for successful parasitism. In the long run, a better understanding of the molecular and cellular bases of CO2-evoked behaviours in parasitic nematodes may lead to new avenues for nematode control. It may also shed light on some of the unique sensory mechanisms that operate in parasitic nematodes to shape parasite-specific behavioural responses.Using a combination of the above approaches, it should be possible to identify the neural mechanisms and molecular pathways that are involved in driving behavioural and physiological responses of


We read with great interest the recent article by Shimazui et al. who concluded that in septic patients, mortality in non-elderly patients was increased with hypothermia and decreased with fever, while mortality in elderly patients was not associated with body temperature (BT) . We woul We read with great interest the letter by Honore et al., concerning the potential confounding effect of continuous replacement therapy (CRRT) on body temperature (BT) measurement. The generally higher risk of developing acute kidney injury (AKI) in elderly patients might also influence the results.2 ). However, non-elderly patients were more frequently initiated on CRRT within first 24 h compared to elderly patients ; non-elderly patients had higher chance of temperature alteration by CRRT. In addition, adding “CRRT” as covariates including previously reported analysis in the Cox regression for the hazard of death over 90 days by the BT adjusted with potential imbalances of age (per year), sex, chronic steroid use, and APACHE II score yielded results similar to the primary findings .As Honore et al. have pointed out, the morbidity of AKI on admission was significantly higher in elderly patients compared to non-elderly patients (elderly 82.5%, non-elderly 73.8%, According to these results, we conclude that the BT, especially hypothermia, may be associated with mortality in non-elderly septic patients including those treated with CRRT, while the association between BT and mortality remains inconsistent in elderly septic patients even after adjusting the CRRT effects.


This editorial summarizes eight research articles included in this supplement issue for the 2020 International Conference on Intelligent Biology and Medicine (ICIBM 2020) conference, that was held on August 9-10, 2020 ,with a topic on data-driven analytics in biomedical genomics. These articles cover a wide range of topics in medical genomics that focus on integrative analysis of genomics data together with other types of data toward understanding complex human diseases,including cancer. With the growing importance of data analytics in biomedical science, we expect this collection of research articles provides scientific discussions in this direction. The 2020 International Conference on Intelligent Biology and Medicine (ICIBM 2020), the official conference of the International Association for Intelligent Biology and Medicine (IAIBM), was held virtually from August 9th to 10th, 2020 due to the COVID-19 pandemic. Established in 2012, the ICIBM conference has grown as a venue to cultivate interdisciplinary research and education at the intersection of bioinformatics, intelligent computing, systems biology, and medical informatics. The first virtual conference of ICIBM (ICIBM 2020) had approximately 300 attendees, with 41 oral presentations scheduled in four live sessions selected from 75 original submissions. With rigorous review for ICIBM 2020 followed by second-round reviews for journal submissions, eight high-quality manuscripts were selected to be published in the ICIBM 2020 BMC Medical Genomics special issue.This supplementary issue includes eight manuscripts that cover a variety of topics in medical genomics, with a focus on data-driven analytics in biomedical genomics research. Here we summarize the contribution of each of these eight manuscripts.In the manuscript titled “A pan-kidney cancer study identifies subtype specific perturbations on pathways with potential drivers in renal cell carcinoma”, Zhan et al.  introducIn the study of “Pinpointing miRNA and genes enrichment over trait-relevant tissue network in Genome-wide Association Studies”, Li et al.  combinedIn the manuscript titled “Characterization of genome-wide association study data reveals spatiotemporal heterogeneity of mental disorders”, Dai et al.  presenteIn “Network-based Drug Sensitivity Prediction”, Ahmed et al.  exploredIn the study of “Differential alternative splicing (AS) between hepatocellular carcinoma with normal and elevated serum alpha-fetoprotein”, Jin et al.  reportedIn the manuscript titled “Integrative analysis of histopathological images and chromatin accessibility data for estrogen receptor-positive breast cancer”, Xu et al.  providedIn the manuscript titled “The circular RNA expression profile in ovarian serous cystadenocarcinoma reveals a complex circRNA-miRNA regulatory network”, Zhuang et al.  studied In the manuscript titled “Conditional transcriptional relationships may serve as cancer prognostic markers”, Yu et al.  incorporThis supplementary issue includes a collection of eight manuscripts that are focused on various perspectives of integrating data across multiple data types , to understand the etiology, prognostics and progression of diseases. With the emerging big data with regards to its volume, velocity, and variety in biomedical science, we anticipate integrative analytics will significantly propel future biomedical advances in realizing the full potentials of big data in biomedicine.


Recently, a growing attention has been observed toward potential advantages of stem cell (SC)-based therapies in regenerative treatments. Mesenchymal stem/stromal cells (MSCs) are now considered excellent candidates for tissue replacement therapies and tissue engineering. Autologous MSCs importantly contribute to the state-of-the-art clinical strategies for SC-based alveolar bone regeneration. The donor cells and immune cells play a prominent role in determining the clinical success of MSCs therapy. In line with the promising future that stem cell therapy has shown for tissue engineering applications, dental stem cells have also attracted the attention of the relevant researchers in recent years. The current literature review aims to survey the variety and extension of SC-application in tissue-regenerative dentistry. In this regard, the relevant English written literature was searched using keywords: “tissue engineering”, “stem cells”, “dental stem cells”, and “dentistry strategies”. According to the available database, SCs application has become increasingly widespread because of its accessibility, plasticity, and high proliferative ability. Among the growing recognized niches and tissues containing higher SCs, dental tissues are evidenced to be rich sources of MSCs. According to the literature, dental SCs are mostly present in the dental pulp, periodontal ligament, and dental follicle tissues. In this regard, the present review has described the recent findings on the potential of dental stem cells to be used in tissue regeneration. Losingal., 2010). One ofal., 2010; Abou Neal., 2010). It canal., 2010). SC-basal., 2010). In thial., 2010). AccordThe SC types ever investigated for application in regenerative medicine can be divided into two categories: embryonic stem cells (ESCs) and adult stem cells (ASCs). ESCs are pluripotent stem cells originating from the inner cell mass of the blastocyst-stage embryos  they are much higher scalable in the undifferentiated state compared to other SC types  is a more general terminology for pluripotent human embryonic stem (hES) cells with stem cell-like developmental quality dda, 2009). The hEdda, 2009), 3) thedda, 2009). Findindda, 2009; Sternbedda, 2009). The cldda, 2009). While dda, 2009). Previodda, 2009). Using dda, 2009).Dental pulp pluripotent stem cells (DPPSCs or DPSCs) originate from the cranial neural crest in the embryonic stage . The isin-vitro or in-vivo, SHED populations can successfully differentiate into various specialized cell populations such as odontoblasts, osteoblasts, chondrocytes, adipocytes, and neural cells   or the primary teeth are among the most studied SC types and the most valuable source of stem cells in tissue engineering studies and cell-based regenerative medicine therapies . The real., 2016). In 200al., 2016). This ral., 2016). The SHal., 2016). Fortunal., 2016). In 200al., 2011). The odal., 2011). More ral., 2016). In thial., 2016; Rosa etal., 2016). The scal., 2016). Tetracal., 2016). in-vitro , drug developments, and inventing novel therapies  have already shown great promises in animal model trials for regenerative treatment of Parkinson's disease and sickle cell anemia . Human al., 2010), and soal., 2012). The iPal., 2012). The hial., 2012). Despital., 2012). Anotheal., 2012). TherefThe stem cells from the apical papilla (SCAPs) belong to a unique SC line locating at the apical tissues of the growing tooth roots when at least two-thirds of the root have formed  were first obtained from the bone marrow of the iliac crest . HoweveEmersion and recovery of dental diseases such as deterioration, is substantially under the effect of the teeth microenvironment, so that any pathologic alteration that can affect the endogenous MSCs' functions and their regeneration capacity may lead to substantial bone loss. Similarly, transplanted exogenous MSCs are highly influenced by the microenvironment of both donor and recipient niches that creates a major challenge to using MSCs for therapeutic regeneration purposes in diseased microenvironments .Adipose tissue-derived stem cells (ASCs) are considered an abundant MSC source that can be obtained through lipectomy or lipoaspiration from different adipose tissues such as the chin, hips, upper arms, and abdomen . The ASEpithelial stem cells and MSC-like cells are reported to locate within particular niches in dental pulp, dental follicle, and periodontal tissues (ligament stem cells) . Dentalal., 2007). Furtheal., 2007). The “tal., 2018). The dental follicle stem cells (DFSCs) are located within the dental follicle or bilayered Hertwig's epithelial root sheath (HERS); they originate from the ectomesenchymal progenitor cell population and differentiate into cementoblasts or osteoblasts (cementogenesis) during tooth root formation . DFSCs in-vitro and in-vivo studies  are a few mesenchymal progenitor cells within the PDL that remain proliferative, and their differentiation potential provides great promises for SC-based regenerative therapies in dentistry . Yet, tal., 2015). PDLSCsal., 2016). PDLSCsal., 2016; Bright al., 2016). In perGingival mesenchymal stem cells (GMSCs) originate from gingival connective tissue, mostly referred to as lamina propria . The giSalivary gland-derived stem cells (SGSCs) were firstly isolated from a rat submandibular gland . Similain-vitro and in-vivo researches imply the mediation of cell chemo-attraction, differentiation, and proliferation in the GFs capability of increasing tissue regeneration capacity  are natural biological molecules with growth-promoting activities that usually have been initially identified for their functions as mediators and regulators in cellular events . Based al., 2011). Despital., 2011; Özdemiral., 2011). Next tal., 2011). Anotheal., 2011). EMD isal., 2011). Considal., 2011). Severaal., 2011). BMP-2,al., 2011). Therefin-vivo and the ex-vivo methods. During the in-vivo strategy, natural healing potential of pulp tissue is elevated by injecting BMP proteins or BMP genes, while in the ex-vivo strategy, DPSCs are isolated and differentiated in the laboratory using BMP proteins or BMP genes. The induced SCs are then transplanted into the tooth  are multi-functional growth factors from the transforming growth factor-beta (TGFβ) superfamily . The gral., 2011).In-vivo study of VEGF in immuno-deficient mice has shown its potential for angiogenesis induction and enhances the survival of subcutaneously transplanted dental pulp cells . The moal., 2008).In-situ hybridization technique has shown that four highly homologous genes encode FGFR family isoforms, which differentially express in dental epithelium and mesenchyme  family consists of 18 receptor-binding members that regulate cellular activities  such asal., 2013, 2017). ). ex-vivIn these SC-based therapeutic strategies that use DPSCs for regenerating dentin-pulp complex, GF concentrations in the dentin matrix should be precisely considered, because they are directly in contact with the pulp and consequently, have a significant effect on DPSCs proliferation as the first stage of pulp repair . The deβ-tricalcium phosphate/type I collagen, gelatin sponge, HA disks, etc.) and successfully achieve regenerated periodontium tissues   that pivotally contribute to embedding the tooth in the jaw, maintaining the tooth homeostasis, repairing, feeding, and also harboring progenitor cell populations called PDLSCs . PDLSCsal., 2011; Han et al., 2011; Ninomiyal., 2011). These al., 2011; Tsumanual., 2011). The tral., 2011; Han et al., 2011); howeveal., 2011; Ninomiyal., 2011). As an al., 2011). In anoal., 2011).2+, and actuate the protein kinase C (PKC) cascade. These mechanisms lead to the migration and preferential adhesion of progenitor cells. The cementum-specific proteins (CEMPs) associated with these activities contain cementum-derived growth factor (CDGF), cementum attachment protein (CAP), and cementum protein-1 (CEMP1). The CEMPs' activity induces the differentiation of periodontal ligament stem cells (PDLSCs), dental follicle stem cells (DFSCs), and, adipose-derived stem cells (ADSCs) into cementoblasts and osteoblasts resulting in periodontium regeneration, PDL fibers formation, periodontal angiogenesis, and creation of a cementum-like mineralized extracellular matrix (ECM)  cells are considered to be cementogenetic and able to produce a thin layer of acellular cementum around the root neck. HERS also can cover the lower part of the root by thicker cellular cementum. A challenge in periodontal regeneration researches using cellular intrinsic fiber cementum (CIFC) is achieving an adequate attachment function. The low-quality attachment of the newly-formed cementum in CIFC is due to lack of acellular extrinsic fiber cementum (AEFC), low density of the inserting fibers, and weak interfacial tissue bonding . In damal., 2019). in-vitro floating sphere assays, and two-dimensional (2D) or 3D cultures of salivary gland cells . The pral., 2017). The SGal., 2017). The ocal., 2017; Paz et al., 2017). Entire-tooth loss can lead to several physical and mental sufferings which may extensively compromise the life quality and self-esteem of the patient. Even, in some wildlife species, losing the complete dentition can end their life. The regeneration of the entire tooth has come to the focus of many pieces of research after successful results of regenerating tooth elements. As a major organ, a tooth is constructed from multiple hard and soft tissues. Enamel, dentin, and cementum are the hard tissues that surround the dental pulp as the only vascularized tissue in teeth . A releal., 2008). Beforeal., 2008). In somal., 2008; Botelhoal., 2008). In a cal., 2008). In anoal., 2008). Also, al., 2008; Kim et al., 2008). Then, al., 2008). Considex-vivo cell manipulation makes cell homing more easily adjustable and more potential to be commercialized for clinical processes. Therefore, this under-recognized strategy can be offered as an alternative to cell-delivery-based tooth regeneration . Cell hal. (201060]) use) useex-val. (2010[60]). Inal. (2010). de novo regeneration of the whole tooth structures . Howeveani, 2014). De noval., 2011). Howeveal., 2011). In craal., 2011). Regardal., 2011). In thial., 2011). Anotheal., 2011). Despital., 2011), and thal., 2011). γ secretion, and promote cytotoxic effects on the virus-infected cells . MSCs cal., 2016). Their al., 2016). MSCs cal., 2016). MSCs cal., 2016). MSCs cal., 2016). MSCs aal., 2016). Regenerative dentistry is increasingly recognized as a state-of-the-art field of medicine among dental clinicians during dental treatments as a procedure of acquiring stem cells  and storing them for potential future autologous treatments. Adult stem cells have been successfully acquired from sources such as oral and maxillofacial regions. For achieving the ultimate purpose, which is craniofacial regeneration, there has remained a long way to be paved for identifying the effective factors in immunomodulatory functions of adult MSCs, BMSCs, and pluripotent stem cells. Such information is required for a more effective outcome of SC-based bone and periodontal tissue restoration, especially for transplanting at the inflamed sites. Knowing the immunomodulatory properties of adult stem cells used in dental and periodontal regeneration is vital for reaching optimal tissue regeneration and controlling the local immune responses during transplantation. Among different strategies in the regenerative dentistry field, tissue engineering and chair-side cellular grafting approaches are more promising because of their more predictable regenerative results. The randomized controlled type of clinical trials with long follow-ups is the most required type of scientific evidence for a comprehensive establishing of reconstructive dental therapeutics. Another necessary field to be elaborated is understanding the biological processes underlying both graft donor and recipient during bone regeneration. Despite all unrecognized aspects of stem cell-based bone and periodontal tissue reconstruction, prosthodontists are increasingly being attracted to stem cell biology because of its successful results as well as the unresolved inefficiencies of implant dentistry. The mechanisms that control the fates and functions of the transplanted stem cells need to be studied. Despite multiple SC-based studies on the dental pulp and periodontal regeneration in animal models, serious considerations, and clinical trials with long-term follow-up are necessary to speed up the translation of basic and preclinical SC-based studies to the dental clinics in terms of regulation, immunity, technology, ethics, and any other possible clinical restriction. These fundamental concerns need to be sorted out to make regenerative treatments practically applicable and beneficial for patients with pathological or injured dental pulp and/or periodontal tissues. Autologous stem cells are already started to be used in some clinical trials for regenerating pulp and periodontal tissues; however, their approval as well as outcomes have not yet been broadcasted and transmitted to the guidelines or indications. Stem cell-based regenerative approaches can help many people around the world who suffer from dentistry complications that strongly warrant further studies. Fortunately, the technologies of modern imaging systems, nanotechnology, and mathematical modeling are increasingly developing and coming to help stem cell-based regenerative studies achieve more reliable and qualitative outcomes in a much shorter time. Mohsen Yazdanian and Hamid Tebyanian  equally contributed as corresponding authors.The authors declare that this work was done by the persons named in this article. Armin Soudi, Mohsen Yazdanian, Reza Ranjbar, Hamid Tebyanian, and Alireza Yazdanian were involved in study design and data collections. Armin Soudi, Mohsen Yazdanian, Reza Ranjbar, Hamid Tebyanian, Elahe Tahmasebi, Ali Keshvad, and Alexander Seifalian were involved in critically reviewing the data and writing the review article.The authors would like to acknowledge the useful comments were given by colleagues at the Research Center for Prevention of Oral and Dental Diseases, Baqiyatallah University of Medical Sciences, Tehran, Iran.There was no financial support.This article is a review and does not contain any experiment on humans or animals performed by any of the authors.The authors declare that they have no competing interests.


Several studies suggested that depression might worsen the clinical outcome of diabetes mellitus; however, such association was confounded by duration of illness and baseline complications. This study aimed to assess whether depression increases the risk of diabetes complications and mortality among incident patients with diabetes.This was a population-based matched cohort study using Taiwan's National Health Insurance Research Database. A total of 38 537 incident patients with diabetes who had depressive disorders and 154 148 incident diabetes patients without depression who were matched by age, sex and cohort entry year were randomly selected. The study endpoint was the development of macrovascular and microvascular complications, all-cause mortality and cause-specific mortality.Among participants, the mean (±SD) age was 52.61 (±12.45) years, and 39.63% were male. The average duration of follow-up for mortality was 5.5 years, ranging from 0 to 14 years. The adjusted hazard ratios were 1.35  for macrovascular complications and 1.08  for all-cause mortality. However, there was no association of depression with microvascular complications, mortality due to cardiovascular diseases or mortality due to diabetes mellitus. The effect of depression on diabetes complications and mortality was more prominent among young adults than among middle-aged and older adults.Depression was associated with macrovascular complications and all-cause mortality in our patient cohort. However, the magnitude of association was less than that in previous studies. Further research should focus on the benefits and risks of treatment for depression on diabetes outcome. Patients with type 1 diabetes mellitus were identified if their ICD-9 diagnostic code was 250.x1 or 250.x3 and they never used oral antidiabetic drug; the patients who remained were categorised into type 2 diabetes mellitus. The first date of antidiabetic prescription was defined as the cohort entry date. Given that some patients delayed treatment and had complications when diabetes was diagnosed, we excluded those with macro- or microvascular complications before or on the cohort entry date (n = 758 041). We did not include patients with a diagnosis of schizophrenia or bipolar disorders (n = 5664). In addition, those with information errors regarding sex, age or mortality date were also excluded (n = 13 259). The study population included 1 087 125 incident patients with diabetes.Using the NHIRD, we identified incident patients with diabetes aged 20 years or more who were firstly prescribed antidiabetic agents and had at least a diagnosis of diabetes mellitus  code: 250.x) between 2001 and 2014 ; major depressive disorder, single episode (ICD-9 code: 296.2x); dysthymic disorder (ICD-9 code: 300.4) or depressive disorder not otherwise specified (ICD-9 code: 311). If a patient has two or more different diagnostic codes of depression, the types of depression were categorised based on the above-mentioned hierarchy. Finally, we identified a total of 38 537 patients with diabetes who had depressive disorders.We identified 154 148 eligible comparison participants with diabetes mellitus, who had no preexisting complications and no diagnosis of severe mental illnesses. For each patient with diabetes who had a depressive disorder, we randomly selected four comparison participants matched by age (year of birth), sex and the cohort entry year. The comparison participants were censored if they were diagnosed with a depressive disorder after the cohort entry date. The details of the selection procedure are shown in et al., et al., The study outcomes included macro- and microvascular diabetes complications, which were identified based on ICD-9-CM diagnostic and procedural codes and the NHI procedural codes from outpatient and inpatient claims records. Macrovascular complications included hospitalisation for acute coronary syndrome (ICD-9-CM: 410.x-411.x) and stroke (ICD-9-CM: 430.x-438.x). Validation of the inpatient diagnosis of the acute coronary syndrome and stroke has been well documented : I00–I99) or diabetes . To test the sensitivity of our methods, we included unnatural death  and suicide .Patients' demographic variables included age, sex and the year of cohort entry. The duration between the first diagnosis of diabetes and the initiation of pharmacotherapy was also measured and categorised into <1 and ⩾1 year. Potential confounders, which were associated with both diabetes complications and depressive disorders, were assessed in the year preceding the cohort entry date, which included comorbid conditions of hypertension (ICD-9 code: 401.x-405.x), dyslipidemia (ICD-9 code: 272.x), chronic pulmonary disease , chronic liver disease  and alcohol- and substance-related disorders . In addition, medication use that reflected underlying medical conditions was assessed, including angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) (ATC code: C09), beta blockers (ATC code: C07), calcium channel blockers (ATC code: C08), lipid-lowering agents (ATC code: C10) and nonsteroidal anti-inflammatory drugs (ATC code: M10).We calculated the incidence of macro- and microvascular diabetes complications and mortality rates based on the event number divided by follow-up person-years. Multivariate Cox proportional hazards models were used with adjustment for the abovementioned confounders, to estimate the hazard ratios (HRs) of depressive disorders for the study outcomes. Subgroup analyses were conducted to evaluate whether the risks of depression for diabetes complications and mortality were modified by types of depression, age, sex and duration between diabetes diagnosis and initiation of pharmacotherapy.post-hoc analyses to evaluate whether there were differences in the quality of diabetes care during the follow-up period between patients who had diabetes, with and without depressive disorder. Indicators of care quality included medication adherence for antidiabetic drugs, frequency of receiving blood sugar testing (HbA1c or fasting blood sugar), lipid profiles, serum creatinine, retina examinations and electrocardiograms during the follow-up period. Antidiabetic drug adherence was measured using the medication possession ratio (MPR), which was defined as the total days of prescribed antidiabetic medication supply divided by the follow-up period. Antidiabetic drug adherence was categorised as poor, irregular and good, based on the MPR .The quality of diabetes care might be a mediator in the association of depression with diabetes complications and mortality; therefore, we did not include these variables in our model. We used p values <0.05.All statistical analyses were conducted using SAS version 9.4 . The statistical significance of relationships was assessed using 95% confidence intervals (CI) or There were 38 537 patients with diabetes who had depressive disorders and 154 148 patients with diabetes with no depressive disorders, as comparison participants. The average follow-up period was 5.5 years (ranging from 0 to 14 years). The mean (±SD) age of participants was 52.61 (±12.45) years, and 39.63% were male. Most of the patients have type 2 diabetes mellitus 99.4%. Among patients with depressive disorders, 26.21% had major depressive disorder, recurrent episode, 15.96% had major depressive disorder, single episode; 48.11% had dysthymia and 9.72% had depressive disorder, not otherwhere classified. Patients with diabetes who had depressive disorders had a higher proportion of comorbid conditions and medication use, except for ACEI/ARB use. The percentage of duration between diabetes diagnosis and initiation of pharmacotherapy ⩾1 year was 17% for patients with diabetes and depression and 24% for comparison subjects see .Table 1v. 2.29 per 1000 person-years), unnatural mortality (2.46 v. 0.77 per 1000 person-years), suicide (1.41 v. 0.27 per 1000 persona-years) and all-cause mortality (21.91 v. 15.96 per 1000 person-years) between patients who had diabetes, with and without depressive disorders. However, there was no difference with respect to microvascular complications and mortality due to diabetes mellitus  for comparison participants. The same was true for the crude incidence of mortality due to cardiovascular diseases , unnatural mortality , suicide  and all-cause mortality  than comparison participants. However, there was no statistically significant difference in microvascular complications and death owing to cardiovascular diseases. We found that depression was associated with a reduced risk of death owing to diabetes .Table 3In subgroup analyses, we found that the magnitude of associations with developing macrovascular complications, unnatural death, suicide and all-cause mortality was higher among those with major depression with recurrent episode than those with dysthymia or depressive disorder, not otherwise specified (the 95% CIs were not overlapping). In terms of the modifying effect of sex, we found that the associations between depression and developing macrovascular complications and unnatural mortality were stronger among women than among men. Otherwise, sex did not have a modifying effect on the incidence of microvascular complications and all-cause and other cause-specific mortality. In terms of age, there were effect modifications on diabetes complications and mortality. HRs in young adults (aged 20–44 years) with depressive disorders for all diabetes complications, all-cause mortality and all cause-specific mortality were higher than those among middle-aged (aged 45–64 years) and older (aged 65 years or more) adults. Furthermore, we found that duration between diabetes diagnosis and initiation of pharmacotherapy had a significant modifying effect on the associations with microvascular complications, diabetes-related death and all cause-mortality; the associations were stronger among patients with duration ⩾1 year than those with duration >1 year.Assessment of the quality of diabetes care showed that patients with diabetes who had depressive disorders had slightly higher proportions of good antidiabetic compliance and higher rates of undergoing screening tests; however, the difference was quite small .Table 4In this study, we found that depression was associated with an increased risk of macrovascular complications, unnatural mortality, suicide and all-cause mortality among patients with incident diabetes mellitus. In contrast, there was no association between microvascular complications and mortality owing to diabetes mellitus and cardiovascular diseases. We found that age had a multiplicative effect modification on such associations. The magnitude of association was higher among young adults than middle-aged and older adults. Regarding the quality of care, we found that patients with diabetes who had depressive disorders had slightly better antidiabetic medication compliance and a slightly higher proportion of undergoing screening tests.et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., The findings of a positive association between depression and macrovascular complications were consistent with those of several previous studies (Black et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., We also found that depression was related to an increased all-cause mortality rate; however, the magnitude was smaller than that found in previous studies (Black et al., et al., et al., et al., et al., et al., et al., et al., We found there was no association between depression and microvascular complications. This finding was against several studies (Black et al., In the subgroup analysis, major depression with recurrent episodes had greater associations with macrovascular complications and all-cause mortality than mild depression. These severity-response relationships further support the hypothesis between depression and diabetes complications. In addition, we found that women had a greater risk for mortality and macrovascular complications associated with depression than men. Previous studies have shown that the effect of diabetes on the risk of coronary disease is significantly greater for women than men (Lee et al., et al., Several limitations should be considered in this study. First, we identified patients with depressive disorders based on claims records. However, some patients with depression were not diagnosed or treated and could be misclassified into the comparison group; therefore, it would introduce bias towards the null. The effect of depression on diabetes complications and mortality might be underestimated. The duration between the diagnosis of depression and diabetes mellitus was unknown; therefore, we could not explore the effect of duration of depression on the study association. Second, only a few patients with type 1 diabetes mellitus were included because the age of onset was generally before 20 years. Our findings could not be concluded for those with type 1 diabetes mellitus due to the limited statistical power. Third, the accuracy of the diagnosis of microvascular complications of diabetes was not yet validated in the NHIRD; however, we used procedural claims data to confirm ambulatory diagnostic codes, or we only used inpatient claims data to minimise the possibility of misclassification. Fourth, several important factors, such as smoking, body weight, exercise, diet control and family history of depression and/or diabetes are not available in the NHIRD. Although we tried to use chronic pulmonary disease, dyslipidemia, hypertension and alcohol or substance use disorders as proxy measures for smoking, obesity and unhealthy lifestyle behaviours, there were still residual confounding effects. Especially, the lifestyle behaviours are time-variant and would be influenced by depression; therefore, these factors need to be adjusted by advanced methodology (Fewell The strengths of this study are the novelty of analysing the associations between depression and diabetes complications among incident patients with diabetes, the elimination of confounding by duration of illness and pre-existing complications, the use of a nationwide representative cohort with clear temporal relationships, a very large sample and a well-defined method for identifying complications of diabetes.In conclusions, we found that patients with diabetes mellitus had a higher rate of macrovascular complications and all-cause mortality when they had comorbid depressive disorders. However, we found a lower adverse effect of depression than the findings of previous studies. This might be owing to the inclusion in our study sample of only incident patients with diabetes, thereby eliminating confounding owing to the duration of illness and preexisting complications. Depression is a modifiable risk factor of diabetes outcome. Further research should focus on evaluating the effect of depression treatment on advanced complications and mortality among patients with diabetes mellitus.


Protein quality control (PQC) systems play essential roles in the recognition, refolding and clearance of aberrant proteins, thus ensuring cellular protein homeostasis, or proteostasis. Especially, continued proliferation and differentiation of stem cells require a high rate of translation; therefore, accurate PQC systems are essential to maintain stem cell function. Growing evidence suggested crucial roles of PQC systems in regulating the stemness and differentiation of stem cells. This review focuses on current knowledge regarding the components of the proteostasis network in stem cells, and the importance of proteostasis in maintaining stem cell identity and regenerative functions. A complete understanding of this process might uncover potential applications in aging intervention and aging-related diseases. Stem cells serve as the origin of a multicellular organism. They can divide to give rise to daughter cells that remain as stem cells or become differentiated with a specific function. The multi-differentiation potential gives stem cells unparalleled advantages in regenerative medicine. Originally, stem cells can be categorized into two main groups: embryonic stem cells (ESCs) and adult stem cells (ASCs). Yet with the development of reprogramming technologies, somatic cells can also be reprogrammed into ESC-like cells, termed as induced pluripotent stem cells (iPSCs). Collectively, ESCs and iPSCs are referred to as pluripotent stem cells (PSCs) because of their high capacity for self-renewal and their ability for multipotent differentiation, offering far-reaching potential in disease modeling and transplant therapies , while such high levels of expression diminish during differentiation  is activated to cope with misfolded proteins, either facilitating their proper re-folding or delivering them for degradation via the proteasome or autophagy pathways  is a central cellular organelle in proteostasis. It is involved in the synthesis, modification, and delivery of proteins to their target sites in the secretory pathway and the extracellular space  is a central regulator, as it plays a vital role in protein folding, ER calcium binding, and regulating the activities of transmembrane ER stress sensors. Consistently, Grp78 homozygous knockout mouse embryos failed to hatch from zona pellucida, and exhibited proliferation defects and extremely high levels of apoptosis in the inner cell mass, demonstrating that Grp78 is crucial for embryonic cell growth and pluripotent cell survival  enhances ER protein folding, thereby increasing the repopulation capacity of hematopoietic stem cells (HSCs) in xenograft assays, connecting the UPR to the maintenance of HSC properties  also plays an important role in the maintenance of stem cell characteristics and homeostasis  increase  plays a crucial role in the self-renewal and differentiation of HSCs and NSCs (Matsumoto et al., Sel1L, reduced self-renewal and resulted in HSC depletion (Liu et al., Taken together, the UPS is essential for maintaining stemness in both PSCs and ASCs, and dysfunction of the UPS may contribute to perturbed stem cell function and fate control. The main differences between UPS-related cellular reactions in stem cells and those in differentiated cells were summarized in Fig. Misfolded and aggregated proteins can also be degraded by a separate autophagy-mediated pathway. Autophagy is a highly conserved intracellular process, in which damaged or unwanted proteins, cytosolic fractions, and organelles are degraded by the lysosome (He and Klionsky, Despite extensive research on autophagy in somatic cell physiology, relatively little is known about the roles of autophagy in stem cell biology. Recent studies report that autophagy is crucial for ESCs and for various ASCs, i.e. HSCs, MSCs, NSCs, and gut stem cells, although with different requirements for its activity (He et al., Apg5 in mESCs causes defects in autophagosome formation and consequent accumulation of proteins in the cytoplasm (Mizushima et al., beclin-1, a mammalian ortholog of the yeast autophagy-related gene 6, die early in embryogenesis, and the autophagic response in mESCs is significantly altered as a result of the beclin-1 deficiency (Yue et al., Ambra1, an autophagy gene, are impaired for neuronal generation (Vazquez et al., In contrast to the high levels of proteasome activity observed during self-renewal, high levels of autophagy activity was exhibited during early differentiation of ESCs and NSCs (Tra et al., Atg7 or Fip200 in the hematopoietic system results in the loss of normal HSC function and death of the mice, suggesting that both autophagy genes are necessary for adult HSC maintenance (Liu et al., Atg3 or Atg7 can inactivate autophagy and restore the expression of 6-photofructo-2-kinase/frutose-2,6-biphosphatase 3, which can in turn restart cell proliferation (Flynn et al., Atg5 plays a key role in the maintenance of HSCs, and the reconstitution ability of Atg5-deficient HSCs in bone marrow of chimeric mice is significantly impaired (Jung et al., Atg5, Atg7, and Atg12 can mediate the self-renewal, differentiation, and regeneration of the muscle and hematopoietic system, and the overexpression of Atg7 can rejuvenate aged satellite cells and HSCs and restore their regeneration ability (García-Prat et al., Different from ESC sand NSCs, in which autophagy activity is required during differentiation, autophagy activity is decreased during the differentiation of MSCs, HSCs, dermal stem cells, and epiblast stem cells (Mortensen et al., Likewise, autophagy is essential for iPSC reprogramming. A distinguishing feature of iPSCs is that the existing number and mass of mitochondria in the somatic cell origins are strikingly diminished during reprogramming. Hence, their metabolic pattern is switched from oxidative phosphorylation to glycolysis and this is considered as an important mechanism in iPSC reprogramming. ATG3-dependent autophagy can act as an executor for mitochondrial clearance during somatic cell reprogramming (Liu et al., Oct4 mRNA (Bradley et al., Previous studies have revealed that genomic and epigenetic stability is essential for stem cell identity. Yet recent years have seen increasing evidence that supported a pivotal role for proteostasis in regulating pluripotency and differentiation of stem cells as well. Under physiological conditions, the proteostasis network is equipped with high versatility in response to distinct stimuli (Balch et al., Furthermore, defects in proteostasis lead to the dysfunction of somatic stem cells, and eventually result in impairment of organismal development and aging, which encourages studies of PQC in search of treatment of aging and aging-related diseases. Pathological conditions, environmental and metabolic stresses, and aging contribute to the production of aberrant proteins in addition to the normal and physiological sources of misfolded proteins (Haigis and Yankner, Study of the regulatory network in proteostasis will also provide new aspects in understanding embryonic development, aging, and pathogenesis. For instance, misfolded proteins have been linked to many neurodegenerative diseases such as Huntington’s disease, Parkinson’s disease, and Alzheimer’s disease, in which aberrant protein aggregates overwhelm the cellular clearance machinery (Bosco et al.,


Small interfering RNA (siRNA) is a class of nucleic acid-based drugs (NABDs) able to block gene expression by interaction with mRNA before its translation. Small interfering RNAs (siRNAs) therefore present extraordinary potential due to their ability to silence the expression of disease-causing genes. Even if the mechanism of action has been successfully investigated (Nobel Prize in Physiology or Medicine 2006 to Andrew Z. Fire and Craig C. Mello “for their discovery of RNA interference – gene silencing by double-stranded RNA”) and siRNA drugs can be candidates to fight, in principle, any diseases. However, the practice of siRNA-based therapies is restricted because of relevant inconveniences. SiRNAs are negatively charged large macromolecules and this entails difficult crossing of cell membranes; they undergo rapid degradation by plasma enzymes and are easily subjected to fast hepatic/renal clearance sequestration. These features seriously hinder siRNAs’ usability in therapeutics. Currently, the scientific community focused on gene therapy research is developing studies to overcome the obstacles related to siRNA’s features.Pharmaceutics titled “Drug Delivery of siRNA Therapeutics” aims to present the state of the art of siRNA delivery, embracing investigation strategies of international research groups with different experiences and skills. The Special Issue will thus be devoted to presenting the current connections between experimental and in silico approaches for therapies based on siRNA delivery, accounting for all the most promising techniques based on liposomes, polymeric and inorganic nanoparticles, aptamers, chemical modification of siRNAs, and so on.This Special Issue of Reviews (five) and research papers (eight) constitute this Special Issue. A representative international scientific community focused on gene-therapies researches is represented by 12 different countries involving 75 scientists with multidisciplinary skills.In the reviews, different research activities cover several disciplines of investigation mainly focused on approaches of siRNA therapies to combat several kinds of cancer in laboratory conditions and the current state of siRNA–lipid delivery systems in clinical trials.In Marson et al.,  studies Research papers deal with experimental new strategies to design and develop innovative suitable and effective vectors for siRNA delivery such as liposomes, dendrimers, aptamers, polymer–lipid systems, polymeric, co-polymeric and magnetic nanoparticles.3O4 nanoparticles prepared for the delivery of therapeutic siRNAs to contrast oral cancer cells’ growth. Craparo et al., [Stiina Kontturi et al.,  aimed th et al.,  studied


The factors associated with suicidal ideation among adolescents have been extensively characterised, but the mechanisms underlying the complexities of the relationship between experiences of childhood trauma and suicidal ideation have been less studied. This study examined the direct effect of childhood trauma on suicidal ideation on the one hand and whether school bullying victimisation and Internet addiction mediate the association between childhood trauma and suicidal ideation on the other hand.This school-based mental health survey was carried out in Qinghai Province in Northwest China in December 2019. We employed standardised questionnaires to collect sociodemographic and target mental health outcomes. Hierarchical multiple logistic regression and structural equation modelling were performed for the data analyses.p < 0.001). School bullying victimisation and Internet addiction mediated the relationship between childhood trauma and suicidal ideation. Internet addiction played a mediating role between school bullying and suicidal ideation.This study included 5864 university students. The prevalence of lifetime suicidal ideation and Internet addiction were 34.7% and 21.4%, respectively. Overall, 16.4% and 11.4% of participants reported experiences of childhood trauma and school bullying victimisation, respectively. There were direct effects of childhood trauma, school bullying victimisation and Internet addiction on suicidal ideation. The total effect of childhood trauma on suicidal ideation was 0.201 (Childhood trauma had both direct and indirect effects on suicidal ideation; these effects were mediated by school bullying victimisation and Internet addiction in Chinese university students. Elucidating these relationships will therefore be useful in developing and implementing more targeted interventions and strategies to improve the mental well-being of Chinese university students. In each university or college, a stratified (according to the majors) random sampling method was used to select the classes, and cluster sampling was then used in each class.Questionnaires were distributed to participants and collected after completion by our study investigators who were uniformly trained prior to the on-site survey. Students who were fully enrolled in the universities were included. A total of 6500 questionnaires were distributed, and 6200 questionnaires were returned, yielding a response rate of 95.4%. Students from Qinghai University, Qinghai Nationalities University, Qinghai Institute Of Health Sciences and Xining Urban Vocational & Technical College accounted for 30.0%, 27.5%, 26.9% and 15.7% of the sample, respectively. Finally, data from 5864 participants were analysed in this study after cases with ⩾ 20% missing data were deleted.et al., The Ethics Committee of the Medical College of Qinghai University approved the study protocol. The survey process followed the principles of anonymity and voluntariness, and all university students involved in this survey provided the informed consent. We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines to report this study , sex , place of residence prior to entering the university (non-plateau/plateau area), ethnicity (Han/others), self-perceived family economic level , only-child status (no/yes), self-perceived weight , self-perceived health , whether in a dating relationship (no/yes) and relationships with classmates, teachers and family (poor/fair/good), was collected.et al., et al., et al., Suicidal ideation (SI) was assessed using the fourth and fifth items of the Beck Scale for Suicidal Ideation (BSS)  , which has satisfactory psychometric properties (Cronbach's ) Young, , 2008, hn) and percentage (%) or the mean and standard deviation (s.d.), as appropriate. Hierarchical multiple logistic regression was carried out to examine the associations between experiences of childhood trauma and suicidal ideation. In step 1, the model was unadjusted by setting suicidal ideation as the dependent variable and childhood trauma as the independent variable. In step 2, adjustments were made for age (years), sex, place of residence prior to entering university, ethnicity, self-perceived family economic level, only-child status, self-perceived weight, self-perceived health status, whether in a dating relationship, relationships with classmates, relationships with teachers or relationships with family. In step 3, school bullying victimisation was added, and Internet addiction was added in the last step. At each step, the R2 change (ΔR2) was used to indicate the predictive power of each group of predictor(s) when adjustments were made for previous predictor(s). A post hoc analysis was performed by reversing steps 3 and 4. The results were expressed with odds ratios (ORs) and their 95% confidence intervals (CIs).The sociodemographic and clinical characteristics were described with the number  .We performed a structural equation model (SEM) to evaluate the hypothesis of the mediating effects of Internet addiction and school bullying victimisation in the relationship between childhood trauma and suicide ideation. Sociodemographic and clinical characteristics that showed statistical significance in step 4 in hierarchical multiple logistic regression were adjusted in the SEM. We used the R lavaan package Rosseel, , and a cs.d. = 1.52) were included in this study. Among the participants, 62.4% were (3657) female, 44.8% (2629) were of Han ethnicity and 79.4% (4656) lived in high-altitude areas prior to entering the university. A total of 5864 university students with an average age of 19.9 years  and 21.4% , respectively. Overall, 16.4%  and 11.4%  of university students reported experiences of childhood trauma and school bullying, respectively.R2 = 0.201, ΔR2 = 0.148). School bullying victimisation, tested in step 3, captured an additional 0.8% of variance in suicidal ideation beyond the effects of basic sociodemographic and clinical factors and the experiences of childhood trauma . When Internet addiction was added in the last step, it yielded an additional 0.8% of the variance , showing that experiences of childhood trauma , Internet addiction  and school bullying victimisation  were positively associated with suicidal ideation. When we reversed the order of entry in the regression model, entering Internet addiction in the third step, school bullying victimisation predicted suicide ideation over and above Internet addiction in the fourth step .β = 0.160, p < 0.001), school bullying victimisation  and Internet addiction  on suicidal ideation. The total effect of childhood trauma on suicidal ideation was 0.201 (p < 0.001). The final SEM also revealed the mediating effects of school bullying victimisation and Internet addiction on the association between childhood trauma and suicidal ideation . School bullying victimisation also had an indirect effect on suicidal ideation which was mediated by Internet addiction . Goodness-of-fit indices  indicated satisfactory fit of the SEM.This study, based on a sample of 5864 university students from parts of the Chinese Tibetan Plateau (i.e. Qinghai Province), allowed us to identify the following: (1) our mental health problems of interest were common among Chinese university students; (2) childhood trauma, school bullying victimisation and Internet addiction had associations with suicidal ideation among the population of interest; (3) there were indirect effects of childhood trauma on suicidal ideation, which were mediated by school bullying victimisation and Internet addiction; and (4) Internet addiction played a mediating role in the relationship between school bullying victimisation and suicidal ideation.et al., et al., et al., et al., et al., et al., At present, suicidal ideation among adolescents is widely concerned around the world (Mortier et al., et al., et al., et al., et al., After adjustments were made for the control variables, hierarchical regression models indicated that childhood trauma, school bullying victimisation and Internet addiction increased the likelihood of having suicidal ideation. We thus conducted SEM by adjusting for sociodemographic factors, personal health factors and dating status, and we identified the direct effect as well as the indirect effect of childhood trauma on suicidal ideation, the latter of which was mediated by school bullying victimisation. Consistently, the direct effect of childhood trauma on suicidal ideation was demonstrated in another Chinese study including 922 freshmen (Shi et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Internet addiction also played a mediating role in the relationship between childhood trauma and suicidal ideation. Childhood trauma and its subtypes, such as emotional, physical and sexual abuse, were reported as factors associated with Internet addiction or Internet gaming disorders in different populations (Dalbudak et al., et al., The findings underscore the importance and necessity of implementing suicide intervention strategies and preventing adverse childhood events and invisible or visible on-campus bullying and Internet addiction. Professional levels of psychological counselling and guidance, mental health education courses, campus safety management and other interventions should be considered and practically implemented (Jimerson and Furlong, In conclusion, this study extended the findings of previous literature by elucidating the direct effects of childhood trauma, school bullying victimisation and Internet addiction on suicidal ideation among university students, as well as the mediating roles of school bullying victimisation and Internet addiction in the relationship between childhood trauma and suicidal ideation. Integrally targeted interventions and strategies that can eliminate and alleviate school bullying events, Internet addiction and the influences of childhood trauma should be developed and implemented to reduce the risk of suicidal ideation and improve the comprehensive mental well-being of Chinese university students.


P < 0.01) and a significant dilution effect (P < 0.01). When considering a subsample of horses treated with macrocyclic lactones only, young horses grazed with cattle had 50% fewer strongyle eggs excreted in their faeces than horses grazed in equine-only pastures (P < 0.01). This is the first evidence of the benefits of mixed grazing with cattle as an alternative to control strongyle infection in horses, although this promising alternative remains largely unknown by horse breeders.Strongyle infection is an important issue in horse breeding. It impairs horse health and performance, with young horses being the most sensitive. Strongyle control has long relied on the systematic use of chemical treatments. However, expanding anthelmintic resistance among strongyles calls for alternative options. Mixed grazing is assumed to reduce strongyle load on the pasture as the result of a dilution effect. This has been shown in small ruminants grazing with cattle, but the putative benefits of co-grazing between horses and cattle have not yet been evaluated. Here, we conducted field surveys and face-to-face interviews on 44 farms from two contrasted saddle-horse production areas, Normandy and northern Massif Central, to compare equine strongyle management practices between specialized systems and mixed horse-cattle systems. Our goals were (i) to quantify breeders’ awareness of the putative benefits associated with the co-grazing of horses and cattle, (ii) to establish whether mixed farming was associated with different strongyle management strategies and (iii) to test whether strongyle egg excretion was reduced in horses grazed with beef cattle. Every breeder relied on systematic calendar treatments, and only 8 out of the 23 mixed breeders were aware that co-grazing of horses with cattle could be used as part of their strongyle control strategy. Management practices were similar across both systems in Normandy. In Massif Central, mixed breeders formed a distinct cluster from their specialized counterparts: deworming was less frequent and stocking density was higher in mixed farms, while specialized breeders seemed more willing to integrate herd and plot management into control strategies. Faecal egg counts measured in horses from Massif Central were significantly reduced when horses were grazed with cattle. This was the result of an increased reliance on macrocyclic lactones in mixed farms ( Horse breeders are increasingly challenged by drug resistance when controlling strongyle infection. Although largely unknown by mixed breeders, alternate grazing or co-grazing with horses and cattle is assumed to reduce strongyle load in pastures as the result of a dilution effect. Here, we reveal a decrease in strongyle egg excretion in young saddle horses grazing with beef cattle. This dilution effect is likely to decrease treatment frequency and thus veterinary costs and environmental side-effects of drug metabolites on dung beetle assemblages.et al., et al., et al., et al., Parasitic infection by strongyle nematodes (mostly cyathostomins) is common in grazing horses. High levels of infection affect horse welfare and performance and can eventually lead to death  to establish if horse breeders integrate herd and grassland management as part of their strongyle control strategy, (ii) to analyse if horse deworming and grazing management differ between mixed horse-cattle and specialized horse farms, and (iii) to quantify strongyle egg excretion in both types of system to determine putative benefits of co-grazing horses with beef cattle.The study was conducted on 44 farms producing saddle horses with or without beef cattle that were selected according to three additional criteria: at least three mares were kept on a farm, farms were located in lowlands  and grasslands represented more than 80% of the agricultural area. Normandy and northern Massif Central were considered as two contrasted case studies: in Normandy, high-level sport horses are bred and grazed on productive grasslands, while in Massif Central, horses are mainly bred for leisure and grazed on less productive grasslands.Face-to-face interviews were carried out on 23 farms from Normandy  and 21 farms from northern Massif Central . Interviews (1 to 2.5-h long according to farm size and the complexity of pasture management) focused on farmer beliefs and practices related to grazing, plot cleaning and animal health management.(i)LU) per hectare, intermediate between 0.6 and 1.0 LU/ha and high between 1.0 and 1.4 LU/ha . To obtain three balanced classes for statistical analyses, annual mean stocking rate was considered low between 0.2 and 0.6 livestock unit ((ii)The proportion of total grassland area in both cut and grazed management  was partitioned into three categories: lower than 30%, intermediate (between 30% and 45%) or higher than 45% of grassland area. Grazing horses on mixed grasslands can strongly decrease numbers of infective larvae in pastures none when strongyle control only relied on a systematic calendar treatment; yes_livestock when additional practices were based on herd management, for example, reducing stocking rate ); (iii) the person in charge of parasite control  and (iv) the anthelmintic class given to young horses and mares.The implemented deworming strategy was also addressed during the interviews. Four variables were covered: (i) the number of anthelmintic treatments administered to young horses , or mares ; (ii) the strategy used for deworming , or systematic plus additional treatments based on faecal egg counts (ERP) indeed varies across anthelmintic classes . A farm was considered of excellent genetic merit when at least one of the mares was registered with a score higher than +9 for one of the genetic indices. A farm was considered of high genetic merit when at least one of the mares was registered with a positive score for one index. All other farms were considered to produce horses for leisure.To test whether FEC was reduced in horses from mixed systems, faeces were sampled in autumn in horses at greater risk of infection (18 to 42 months old). For logistical reasons and according to breeders’ willingness to participate, the sampling took place on Massif Central farms only.n = 23 horses, 6 farms) or alone in a specialized farm . Fresh individual faeces were collected on the ground and kept at 4°C for less than 48 h; eggs were counted (test sensitivity: 15 eggs/g) at the official local veterinary services (DDCSPP du Puy de Dôme), based on sedimentation and concentration by a flotation technique  on farming system (two classes), the number of treatments (three classes), the proportion of time each horse spent on mixed grasslands, grassland stocking rate and time since the end of the ERP. A variable selection procedure was implemented with the stepAIC function of the MASS package that retained the farming system, the time since the end of ERP and stocking rate.To establish whether FEC was significantly associated with the farming system, a linear regression was performed. We built a full model regressing FEC  and mixed systems (n = 19). For all statistical analyses, effects were considered significant when the P-value was lower than 0.05.In a second analysis, we considered a subsample of 28 horses treated with macrocyclic lactones only. A two-sample n = 33 farms; moxidectin n = 22 farms). Additional herd and grassland management practices were implemented and considered as part of breeders’ strongyle control strategy in a total of 18 farms, 11 from Massif Central and 7 from Normandy.Face-to-face interviews were also undertaken to evaluate the general beliefs and awareness regarding parasite control management in both mixed and specialized systems. Strongyle control relied on a systematic calendar treatment in all 44 farms surveyed. The most commonly used anthelmintics were fenbendazole (in 36 farms) and macrocyclic lactones  and included pasture liming (n = 5), use of rotary slashers (n = 5) or dung-spreading harrows (n = 4), avoiding rapidly returning herds to the same pasture (n = 3) and removing dung from pastures (n = 1). The sum is higher than 14, as some breeders used 2 of these grassland management practices.Plot-cleaning practices were the most common , two-thirds of which were mixed cattle-horse farms and one-third specialized horse farms. Remaining clusters, named MC-mix and MC-spe, were mostly composed of mixed (70%) or specialized (83%) farms from northern Massif Central, respectively. This suggests that practices were different between mixed and specialized systems in Massif Central, whereas practices were much more similar across systems in Normandy.Following the analysis of breeders’ awareness, we attempted to summarize their strategies in order to establish whether mixed farming systems were associated with particular practices. Multiple correspondence analysis applied to management practice data revealed three clusters separated along two axes explaining 13.0% and 10.6% of total variance, respectively. The first cluster, named Nor, included 22 farms, mainly in Normandy  but not stocking rate . Farming system was also associated with a significant difference in FEC , with horses from the mixed farming systems excreting half as many eggs than their counterparts from specialized farms.FEC was conducted on 46 horses from mixed and specialized farms to establish whether farming system was impacting horse excretion and what variables underpinned this variation. Our regression model found that time since the end of ERP was significantly driving observed variation in FEC (P < 0.01; Figure A second analysis was performed on a subsample of 28 horses last treated with macrocyclic lactones. It confirmed that young horses grazed with cattle had 50% fewer strongyle eggs excreted in their faeces than horses grazed in equine-only pastures (et al., et al., et al., The purpose of our study was to compare specialized saddle horse farms with mixed horse-cattle farms and to establish whether any difference in parasite control could be found. The limited awareness of the putative beneficial effects associated with the co-grazing strategy was striking, especially because mixed grazing is a key pillar of integrated parasite management in agroecological grassland-based systems (Dumont et al., et al., et al., et al. This lack of awareness regarding mixed grazing was also associated with the widespread use of fenbendazole, despite high prevalence of resistant strongyle populations in France (Traversa et al., et al., A key finding from our surveys is that specialized horse breeders from Massif Central seemed more willing than the mixed breeders to integrate herd and plot management into their control strategies. In these farms, the proportion of grasslands under both cut and grazed management was also the highest, and early cuts under mixed management are known to strongly decrease the number of infective larvae in pastures (Martin-Rosset, et al., et al., et al., et al., et al., et al., While our results are thus likely influenced by regional context, they also provide the first indication that the co-grazing of horses and cattle has beneficial effect for equine strongyle control. Our results are consistent with previous observations in ruminant farming, showing that simultaneous grazing by cattle and sheep (Southcott and Barger, We provide the first evidence of a decrease in the parasite burdens of young saddle horses grazing the same pastures as cattle in mixed farms, compared with horses grazing alone in specialized systems. This opens a promising alternative for controlling horse parasitic infection that remains largely unknown by horse breeders. Association between horses and cattle at pasture is facilitated through the use of the same type of fencing for the two species, with possible limitations due to injury risks which could be solved through alternate grazing. This suggests a diversity of more sustainable agroecological parasite management strategies in horse farms as alternatives to repeated chemical treatment, which raises serious resistance issues.


The current status and ongoing development of 3D electron diffraction and microcrystal electron diffraction in macromolecular crystallography are reviewed. Microcrystal electron diffraction (MicroED) has recently emerged as a promising method for macromolecular structure determination in structural biology. Since the first protein structure was determined in 2013, the method has been evolving rapidly. Several protein structures have been determined and various studies indicate that MicroED is capable of (i) revealing atomic structures with charges, (ii) solving new protein structures by molecular replacement, (iii) visualizing ligand-binding interactions and (iv) determining membrane-protein structures from microcrystals embedded in lipidic mesophases. However, further development and optimization is required to make MicroED experiments more accurate and more accessible to the structural biology community. Here, we provide an overview of the current status of the field, and highlight the ongoing development, to provide an indication of where the field may be going in the coming years. We anticipate that MicroED will become a robust method for macromolecular structure determination, complementing existing methods in structural biology. However, the rate-limiting step in macromolecular crystallography inhibiting structure determination is often crystallization  can make use of such small protein microcrystals by outrunning the radiation damage using a diffraction-before-destruction scheme. SFX data are collected using an X-ray free-electron laser (XFEL), which generates brief and highly intense X-ray pulses on a femtosecond timescale, taking single still diffraction snapshots of partial reflections from individual hydrated microcrystals before the sample is destroyed micrometre-sized crystals can be obtained from proteins that are well below 50 kDa  was determined in 2013  occur more frequently with increasing crystal thickness and will affect structure determination  milling  cannot be separated from kinematic scattering. Because of dynamical scattering, weaker reflections on average will appear more intense. As a result, the first-order kinematic approximation that is used in structure refinement is no longer valid. An effective way to minimize dynamical scattering is to carefully select thin crystals  for data collection. The crystal thickness ideally should not exceed much more than about 200 nm (Subramanian 4.3.et al., 2018et al., 1999et al., 2015et al., 1996et al., 1999et al., 2015Electrons are charged particles and interact with the electrostatic potential of the crystal (Cowley, 19954.4.ab initio phasing of short peptide fragments (Sawaya et al., 2016et al., 2018et al., 2020de novo phasing of protein structures using electron diffraction has not yet been achieved. The anomalous signal may be too insignificant for experimental phasing using anomalous dispersion (Cowley, 1995To date, all structural models of proteins determined by MicroED have been phased using molecular replacement. Direct methods can be used for electron diffraction data (Dorset & Hauptman, 19764.5.et al., 1999et al., 2005et al., 1984et al., 1990et al., 1992et al., 1996et al., 1998et al., 2003et al., 2013et al., 2020In 2D electron crystallography, reconstructions from TEM images can be combined with high-resolution electron diffraction patterns for structure determination (Unwin & Henderson, 19754.6.et al., 2019et al., 2020et al., 2018et al., 2020et al., 2019et al., 2020− Å−2 was found to have an optimal signal-to-noise ratio (Bücker et al., 2020In macromolecular crystallography, the total electron dose limits the maximum attainable resolution and data quality. Using the continuous-rotation method in MicroED, the critical accumulated dose is spread out over an entire tilt series to sample a substantial wedge in reciprocal space. In contrast, in SFX only single snapshots are recorded from tens of thousands of individual crystals (Schlichting, 2015et al., 2013et al., 2020et al., 2019In SerialED, only a single still diffraction pattern of a randomly orientated crystal is acquired, lacking information about unit-cell parameters owing to the large Ewald sphere. This limitation can be overcome by automation, collecting and integrating data from many thousands of randomly oriented crystals (White 5.de novo phasing through experimental phasing and/or high-resolution imaging may be realized in the years to come. We anticipate that with these advances, MicroED will play an ever more important role in macromolecular crystallography.Here, we illustrate the various achievements made by MicroED in the past years, and discuss the novel opportunities that it may bring for structural biology. Recent successes include determining increasingly challenging structures, resolving ligand-binding interactions and enabling structure determination of membrane proteins from microcrystals embedded in lipidic mesophases. The field is still evolving, and improvements in specimen preparation, optimization of TEM hardware and accurate modelling of the electrostatic potential are needed. Even more so,


Antimicrobial resistance (AMR) is a threat to public health O'Neil, . AMR occDrug‐resistance infections contribute to longer hospital stays, higher medical costs and increased incidence of morbidity , 23,000 deaths and two million illnesses were caused by antibiotic‐resistant bacterial infections (Centers for Disease Control, (Zetts et al., . Researchers have found that approximately 154 million primary care visits in the United States result in an antibiotic prescription and approximately 30 per cent, or 47 million, of these prescriptions are not necessary (PEW, One of the main risk factors for AMR in the United States is inappropriate prescription of antimicrobial therapies by primary care providers ary PEW, .(Zetts et al., . However, people in extremely rural communities in the United States tend to wait longer before seeing a provider for treatment for upper respiratory symptoms (Morgan & Hart, Researchers have shown that patients’ demand for antimicrobial therapies varies depending on cultural background and geographic location (Larson et al., 2Interventions at the primary level are needed long term to prevent the spread of AMR (Centers for Disease Control, Appropriate nursing interventions at the primary level are also needed to overcome cultural and geographic barriers (Hicks et al., 3Researchers have demonstrated that the primary level of prevention of AMR has a clear impact and is cost‐effective (Ball, Dains, Flynn, Solomon, & Stewart, All authors contributed equally to this article.


Breast cancer is the most frequently diagnosed cancer type and the second leading cause of cancer-related deaths among women worldwide. The causes of breast cancer are not yet fully known, although a number of risk factors have been identified. Tumor biomarker is a term used to describe potential markers of cancer development and progression. As we explore these biomarkers further, we must try to understand the underlying mechanisms of tumor development, as we move along the path to discovery of novel therapies that will increase our ability to offer personalized patient care in the future. With the migration of advanced high throughput technologies, such as Next Generation Sequencing from clinical practice, biomarker research and discovery are poised to explode once again. Translation of novel biomarkers into clinical practice and diagnostic laboratories is coupled with regulatory and administrative requirements that must be met, while collaboration between research institutions, industry, and the private sector drives further advancements in the field of breast cancer biomarker discovery and application.N-Acetyltransferase 1 Knockout Elevates Acetyl Coenzyme A Levels and Reduces Anchorage-Independent Growth in Human Breast Cancer Cell Lines” by Stepp et al., “Overexpression of Kynurenine 3-Monooxygenase Correlates with Cancer Malignancy and Predicts Poor Prognosis in Canine Mammary Gland Tumors” by Chiu et al., “Notch Signaling Activation as a Hallmark for Triple Negative Breast Cancer Subtype” by Giuli et al., and “Human Mitotic Centromere-Associated Kinesin is Targeted by MicroRNA 485-5p/181c and Prognosticates Poor Survivability of Breast Cancer” by Lu et al. contributed different biomarkers of breast cancer which may help to assess prognosis or predictive indicators. The focus of the third group of articles is on genetic mutations in breast cancer. The paper titled “Association of ESR1 Mutations and Visceral Metastasis in Patients with Estrogen Receptor-Positive Advanced Breast Cancer from Brazil” by Reinert et al. observed an association of ESR1 mutations with metastasis. The paper titled “Role of Four ABC Transporter Genes in Pharmacogenetic Susceptibility to Breast Cancer in Jordanian Patients” by AL-Eitan et al. proposed the ABCB1 mutation associated with breast cancer in Jordanian Arabs. The paper titled “A Review of the Hereditary Component of Triple Negative Breast Cancer: High- and Moderate-Penetrance Breast Cancer Genes, Low-Penetrance Loci and the Role of Nontraditional Genetic Elements” by Ellsworth et al. described genes and genetic elements, which have been associated with increased risk of triple negative breast cancer. The paper titled “Pregnancy Hypertension and a Commonly Inherited IGF1R Variant (rs2016347) Reduce Breast Cancer Risk by Enhancing Mammary Gland Involution” by Powell et al. observed that statistically significant decrease in terminal duct lobular unit counts signifies increased breast epithelial involution in women with prior hypertension who inherited the TT genotype of IGF1R SNP (rs2016347).The aim of this special issue is to provide new findings regarding molecular pathways and biomarkers that could improve the diagnosis and the prognostic classification of breast cancers, their application in the clinical setting, and their potential utility in personalized patient therapy. The total of submissions is 50. After single-blind peer review by at least two reviewers, 14 papers were finally accepted to be published. The accepted rate is 28%. The average number of authors for each accepted paper is 7. The affiliated institutes of the authors are from Brazil, China, Italy, Iraq, Jordan, Portugal, Spain, Saudi Arabia, Taiwan, the UK, and the USA. These accepted papers can be organized in different groups. The focus of the first group of articles is on prognosis and therapy in breast cancer. The findings of the paper titled “Exploring the Role of Breast Density on Cancer Prognosis among Women Attending Population-Based Screening Programmes” by Domingo et al. reveal that increased breast density was associated with worse survival outcomes among women participating in breast cancer screening. The paper titled “Attenuated Total Reflection-Fourier Transform Infrared (ATR-FTIR) Spectroscopy Analysis of Saliva for Breast Cancer Diagnosis” by Ferreira et al. showed ATR-FTIR spectroscopy can be used in saliva samples to discriminate breast cancer patients from benign patients and healthy subjects. The paper titled “Dovitinib Triggers Apoptosis and Autophagic Cell Death by Targeting SHP-1/p-STAT3 Signaling in Human Breast Cancers” by Chiu et al. has provided the evidence for anticancer effect of dovitinib to suggest it as a potential target for breast cancer therapy. The focus of the second group of articles is on biomarkers in breast cancer. The paper titled “A Novel Role for Cathepsin S as a Potential Biomarker in Triple Negative Breast Cancer” by Wilkinson et al. investigated the expression profile of Cathepsin S in breast cancer patients. The paper titled “Identification of Cell-Free Circulating MicroRNAs for the Detection of Early Breast Cancer and Molecular Subtyping” by Souza et al. identified the molecular signature miRNA as noninvasive biomarkers in patients with breast cancer. The paper titled “CD133 in Breast Cancer Cells: More Than a Stem Cell Marker” by Brugnoli et al. reviewed the value of CD133 as prognostic factor of malignant progression of breast cancer. The other four papers titled “In summary, the research papers cover a wide range of applications including potential diagnostics, predictions, and treatment. Furthermore, this special issue also includes regional genetic mutation, breast density on cancer prognosis, small RNA as a biomarker, surface marker of cancer stem cells, potential marker of cancer metastasis, and spectroscopy predicting the rate of cancer. This may be helpful in assessing prognostic or predictive indicators, as well as developing new therapies and new insights aimed at improving breast cancer.Chia-Jung LiHui-Ming ChenJi-Ching Lai


Critical comment on the review by Okada et al. on the effect of early versus delayed mobilization because of their definition of early mobilization as mobilization within a week of ICU admission in contrast to current evidence. In their systematic review and meta-analysis, Okada et al. investigate the impact of early versus delayed mobilization for in-hospital mortality and health-related quality of life among critically ill patients, including 11 studies in their meta-analysis [Aware that there is no uniform definition of “early mobilization” in the ICU yet, to use 1 week as cut-off point seems unreasonable for various reasons. So far, only studies starting early mobilization within 72 h have been able to improve patient outcomes, as summarized in published narrative reviews . SchweicAnother current meta-analysis using different definitions was able to show an effect of early mobilization . FinallyIn conclusion, as timing seems crucial for patient-centered outcomes, early mobilization should be consistently defined as mobilization within 72 h of ICU admission.