Recent microRNA (miRNA) expression profiling studies suggest the clinical use of miRNAs as potential prognostic biomarkers in various malignancies. In this study, aiming to identify microRNAs with prognostic value for overall survival (OS) in stomach adenocarcinoma (STAD) patients, we analyzed the miRNA expression profiles and the associated clinical characteristics in 380 STAD samples from The Cancer Genome Atlas (TCGA) dataset. An eight-miRNA signature for predicting OS in STAD patients was identified and self-validated by survival analysis and semi-supervised principal components method. We developed a linear prognostic model composed of these miRNAs to divide patients into high- and low-risk groups according to the calculated prognostic scores. Kaplan-Meier analysis demonstrated that patients in the high-risk group had worse OS compared with patients in the low-risk group. Notably, this miRNA prognostic model showed prognostic significance to the STAD patients in early stages and the chemo-resistant patients, who would potentially benefit from additional medical interventions. Finally, this eight-miRNA signature is an independent prognostic biomarker and demonstrates a good predictive performance for 5-year survival. Thus, this signature may serve as a novel biomarker for predicting survival as well as chemotherapy response in STAD patients. Gastric cancer (GC) represents a major health problem worldwide, ranking the fifth most common malignancy and the third leading cause of global cancer mortality . Early dIn recent years, various miRNAs and their targets have been found to be dysregulated in cancer. Due to the stability and expression specificity of miRNAs in different tissues, there is increasing evidence to suggest that they can serve as novel prognostic biomarkers with potential clinical significance for various cancer types. Thus far, dysregulation of miRNAs in GC has been reported to be associated with histology, Epstein-Barr virus infection, chemotherapy, and metastasis –11. A nuWith the advent of next-generation sequencing and bioinformatics as well as the launches of large-scale cancer genome projects, such as The Cancer Genome Atlas (TCGA), comprehensive and multi-dimensional maps of the key genomic and epigenomic changes in cancer can be readily achieved and accessed. Bioinformatic analysis of TCGA datasets has been shown to be an outstanding tool in identifying genetic and epigenetic changes related to clinical outcomes, thus opening a new avenue for the discovery of novel prognostic markers for various malignancies , 21. In n = 190) and testing set (n = 190). No significant difference in clinical covariates was observed between the two sets . Among these, 77 miRNAs (55.8%) were up-regulated, including miR-1269 and miR-196a-1, which exhibited > 5-fold increased expression. Conversely, 61 miRNAs (44.2%) were down-regulated, including miR-490 and miR-1-2, which showed 4.8-fold and 3.5-fold reduced levels in STAD, respectively  and three were shown to be protective . We then developed a miRNA prognostic model for predicting 5-year survival in the training set, by which the samples were classified into high-risk or low-risk groups using the optimum cutoff point of miRNA scores according to ROC curve. Figure p < 0.001, using the log-rank test, Figure p < 0.001, using the log-rank test, Figure Using the optimum cutoff value obtained from the training set, patients were assigned into high-risk and low-risk groups. The ability of prognostic prediction of the eight-miRNA signature was examined in the testing set and the entire STAD cohort, respectively. Kaplan-Meier analysis revealed that patients in the high-risk group had poor OS, compared with patients in the low-risk group in both testing set (n = 179). Kaplan-Meier analysis revealed that patients in the high-risk group associated with worse OS . Thus, this eight-miRNA signature could distinctly predict the survival for STAD patients in an early stage, suggesting that it could have potential clinical value for help in guiding additional medical interventions to this patient subgroup. .It is often challenging to distinguish chemoresistant STAD patients from those that have good responses to chemotherapy. In order to evaluate the prognostic value of the eight-miRNA signature to chemotherapy response in STAD patients, we applied the eight-miRNA signature to the 112 patients, whose post-operative chemotherapy responses were recorded in the TCGA STAD cohort. Using our eight-miRNA prognostic model, the 112 patients were divided into low-risk and high-risk subgroups according to their responses to chemotherapy. As shown in Table We also examined the association of eight-miRNA signature with clinical characteristics in STAD patients. No significant differences were observed when patients were stratified by gender and age .p < 0.001).We further conducted a multivariate analysis to evaluate the independent prognostic value of the eight-miRNA signature. Age, gender, Grade, T stage, N stage, M stage and the miRNA signature were used as covariates. The Cox multivariate regression analysis revealed that the miRNA signature is an independent prognostic factor associated with OS , demonstrating the predicted miRNA targets are involved in many important pathways associated with cancer development, including adherent junction, Wnt, TGF-beta, VEGFR and MAPK signaling pathways  categories and Gene Ontology (GO) categories. As shown in MiRNAs are 22–26 nucleotides small RNAs that play vital roles in modulating gene expression at the post-transcriptional level by binding to the 3′ or 5′ untranslated region of targeted mRNAs. Here we found 138 miRNAs were differentially expressed between STAD and adjacent normal tissues, among which 17 miRNAs levels were associated with at least two of following histopathological factors: T stage, lymph node metastasis, distant metastasis and tumor grade. Using survival analysis and semi-supervised principal components method, an eight-miRNA signature  for predicting OS of STAD patients was identified and self-validated in a large cohort. Importantly, this eight-miRNA signature was further confirmed to be an independent prognostic factor. Furthermore, with respect to the association between their expression levels and patient survival, the eight miRNAs in the signature were divided into two groups: five risky miRNAs that were negatively associated with the survival and three protective miRNAs which were positively associated with the survival.Among the five risky miRNAs , overexpression of miR-145 has been reported to be a key factor for the prediction of poor overall survival in bladder cancer . HoweverAmong the protective miRNAs , deletion of mir-1537 has been reported in aggressive neuroblastoma . During It is of note that this eight-miRNA prognostic model could predict the high-risk patients in early stages (stage I–II), which accounts for approximately 10% of all STAD recurrences . These pin silico analysis proved that the eight-miRNA signature is biologically meaningful. Specifically, Ago2, the co-target of miRNA-145, miR-184 and miR-802, played an important role in GC differentiation, lymph node invasion and clinical stage [Bioinformatic analysis of potential and validated targets of miRNA and the subsequent analysis of KEGG pathways clustered by target genes are promising strategies for gaining insights into plausible biomarkers and key events involved in cancer development and progression. Enriched KEGG pathway analysis of the eight-miRNA model indicated that both predicted and validated target genes of this miRNA signature were clustered in cancer-associated KEGG pathways. Furthermore, our al stage . Myc, a al stage . Moreoveal stage . CertainIn summary, using integrated bioinformatic analysis of the largest available cohort of STAD patients and the corresponding genome-wide miRNA sequencing results, we identified a specific eight-miRNA signature that could serve as an independent prognostic factor for the prediction of OS in STAD patients. However, before this finding can be applied to clinical practice, further validation in independent large cohorts is required in the future.Level 3 of 1049 miRNAs expression profiles in stomach adenocarcinoma (STAD) patients and their clinical information dataset were downloaded from The Cancer Genome Atlas (TCGA) data portal (March 2016). To exclude unrelated causes of death, only patients with follow-up longer than 1 month were included in the subsequent analysis.p < 0.05) were considered as differentially expressed miRNAs and were selected for further analysis.The raw counts of miRNA expression data of 41STAD with their paired normal tissue were obtained from the TCGA dataset (Illumina HiSeq Systems). MiRNA-expression data was normalized by the R/Bioconductor package edgeRv . The expp < 0.0.5 as the cutoff.The semi-supervised method which combines both the gene expression data and the clinical data was used to identify candidate miRNAs with prognostic value , 38. UniAn importance score was calculated by the supervised principal components method and was assigned to each miRNA . Ten-folwww.mirecords.biolead.org) database, which offers a comprehensive data of possible miRNA-targets of 11 different data sets. The pathway enrichment analysis was conducted with the GeneTrail gene set enrichment tool. The results were considered significant when the p-value was less than 0.05 after FDR corrected [The list of predicted target genes of the candidate miRNAs was obtained from miRecords v4.0 (orrected , 40.


Leukaemia inhibitory factor (LIF) plays a critical role in “stemness” versus “differentiation”, a property that underpins the core value of LIF as a therapeutic for both the treatment of autoimmune disease and for promoting tissue repair. This value can be realized using nano-engineering technology, where a new generation of tools can, with unprecedented ability, manipulate biological functions. One striking example is the treatment of multiple sclerosis (MS). The underpinning biology is the newly identified LIF/IL-6 axis in T lymphocytes, which can tilt the behaviour between immune tolerance versus immune attack. This LIF/IL-6 axis is ideally suited to nanotherapeutic manipulation, given its inherent mechanistic simplicity of two mutually opposing feed-forward loops that determine either tolerogenic (LIF) or inflammatory (IL-6) immunity. Using LIF that is formulated in biodegradable nanoparticles (LIF-NP) and targeted to CD4+ T cells, the axis is harnessed towards immune tolerance. This has implications for the treatment of autoimmune diseases, where the clinical burden is immense. It encompasses more than 100 diseases and, in the USA alone, costs more than $100 billion in direct health care costs annually. Other properties of LIF include the promotion of healthy neuro-glial interactions within the central nervous system (CNS), where, in addition to MS, LIF-NP therapy is relevant to inflammatory neurodegenerative diseases that represent a large and increasing need within aging populations. Thirdly, LIF is a reparative growth factor that can maintain genomic plasticity. LIF-NP supports the use of stem cell-based therapies in regenerative medicine plus augment therapeutic benefits within the patient. These core properties of LIF are greatly amplified in value by the advantage of being formulated as nanoparticles, namely (i) targeted delivery, (ii) exploitation of endogenous regulatory pathways and (iii) creation of surrogate micro-stromal niches. We discuss LIF-NP as a means to harness endogenous pathways for the treatment of MS, both to reset immune self-tolerance and to promote repair of myelin that is required to support health within the nervous system. We consider the value of the targeted delivery of a stem cell growth factor called “leukaemia inhibitory factor” (LIF) in the context of LIF's biologic properties which are directly relevant to the treatment of multiple sclerosis (MS).Nanomedicine is a new era in therapeutics, which has been enabled by fundamental advances in biology combined with progress in biocompatible nanotechnology. Nanotechnology provides access to three highly desirable therapeutic aims, namely (i) Why LIF? Firstly, LIF is a multi-functional cytokine that is involved in regulating the plasticity of a genome [for example, protective role for LIF has recently been discovered [As a therapeutic, the second attraction of LIF is its role in the adaptive immune system. Here, T lymphocytes, each expressing a unique antigen-specific receptor, provide the full repertoire of antigen recognition of an individual plus the exquisite specificity of the adaptive immune response. Failsafe mechanisms ensure that the power of an immune attack is restricted to invading pathogens. Should these mechanisms malfunction, then an immune attack against the body's own tissues will lead to autoimmune disease and possibly even death. An autoimmune scovered –8. Here,also directly opposes interleukin-6 (IL-6) [In the adaptive immune system, the finding that LIF, in addition to promoting Treg and self-tolerance, 6 (IL-6)  is of propposing feed-forward loops of gene expression are activated by LIF versus IL-6. The expression of gp190, the LIF-specific sub-unit of the LIF receptor, provides a pivotal mechanism for the axis  might cooperate ytokines , 9–10 – ytokines . Althougin vivo [A short half-life normally attenuates cytokine activity in vivo  and thisin vivo  or humanin vivo , or by gThe development of the LIF-PLGA nanoparticle (LIF-NP) was based on strategic reasoning. The polymer poly(lac-tide-co-glycolide) (PLGA) is already approved by the FDA for drug delivery applications due to its safety, excellent biocompatibility and “tunable” release rates. In nanoparticulate form, PLGA decorated with functional avidin groups on the nanoparticle surface, enables the modification of this surface through the robust attachment of biotinylated ligands such as PEG , T cell-versus IL-6-NP, provided extracellular cues able to control T cell maturation via the lineage-determining master genes, FOXP3 (Treg) and RORγt (TH17), respectively [can LIF-NP directly oppose the IL6-driven pathway? If yes, then the targeted delivery of LIF by LIF-NP may guide tolerogenesis – even in the face of a local inflammatory IL-6-rich micro-environment as occurs in TH17-linked autoimmune activity. The actual dose of cargo being delivered when using nanoparticles is extremely low: one milligram of PLGA nanoparticles carries around one nanogram LIF cargo. However, LIF, when formulated as LIF-NP, was >1000-fold more potent than soluble LIF. When delivered as LIF-NP, 200pg LIF opposed the effect of 20,000pg soluble IL-6, preventing RORγt induction. Indeed, a recent mathematical model estimated that the potency of a drug or cytokine could be increased by several orders of magnitude when the cytokine is delivered via a biodegradable particle targeted to T cells [For the prototype, the end point of success was the demonstration of (i) target-specific delivery of cytokine; (ii) retained bioactivity specific to the released cytokine cargo; and (iii) a biological response specific to the targeted cells. All of these benchmarks were met when exploiting the LIF / IL-6 axis as a stringent model to prove bio-efficacy in a study by Park et al. . When taectively –22. Cell T cells in vivo? The answer is yes. Firstly, CD4-targeted LIF-NP biased the in vivo immune response towards tolerance, as measured in transgenic GFP-FOXP3 mice. The relative numbers of antigen-specific FOXP3+CD4+ T cells increased following the donor-specific transfusion (DST) of LIF-NP-coated cells targeted to CD4. This effect was in marked contrast to the use of IL-6-nano-treated lymphocytes in the DST system, where no increase of FOXP3+ cells occurred. Thus, the expansion of antigen-specific FOXP3+ cells was confirmed as being due to the specific bioactivity of LIF-nano and not a function of the delivery system itself. A more stringent test used mismatched vascularized heart allografts in mice. Here efficacy was also seen with LIF-NP treatment prolonging activity of the beating-heart graft.The next relevant question was, do the LIF-NP work Overall, the Park study  showed tMultiple sclerosis (MS) is a T cell-mediated inflammatory demyelinating disease of the human central nervous system (CNS). It is the most common disease of the CNS that affects young adults. Onset occurs between 20 – 40 years of age and the worldwide incidence is 2.5 million, with 2,500 cases being diagnosed each year in the UK alone. Scotland has the highest incidence of MS worldwide, with 1 in 170 women on the Orkney Islands being affected. Although the cause remains unknown, predisposing factors include being female and Caucasian, whilst the higher incidence in the northern and southern hemispheres suggests a link to vitamin D deficiency due to low sunlight, vitamin D being important in Treg-mediated self-tolerance –26. For Treatment for MS is highly challenging. Not only must autoimmunity be reset to self-tolerance but also the structural damage to the demyelinated nerves must be repaired. The two are inextricably linked, since it is the immune-mediated demyelination of nerve axons that causes the neurological symptoms of MS. The loss of myelin's function for efficient electrical conductance along nerve axons, combined with the loss of myelin-derived metabolic support for the axon, eventually leads to the death of the nerve itself. In most cases, MS initially develops with alternating relapses and remissions of symptoms that reflect repeated waves of autoimmune neuro-inflammation. However, over time, nerve death increases, leading to irreversible progressive disease. In a few cases, the disease is immediately progressive. In the relapsing form, early remissions occur because the demyelination can be repaired endogenously (remyelination), restoring fast nerve axonal impulse conduction, together with protection and support of the axon. However, this myelin repair is inefficient and, over time, fails. Thus, although immunosuppressive therapies can reduce the probability of new relapses , 28, theSince the removal of myelin renders axons metabolically non-viable, there is an intense need to understand the mechanisms by which myelin repair either occurs or fails. If LIF proves reparative, then therapy that uses LIF-NP becomes of prime importance. To date, we know that the natural repair pathway for remyelination of demyelinated axons involves endogenous oligodendrocyte precursor cells (OPCs). OPCs respond to demyelination by proliferation and migration to the area of damage; here they then differentiate into mature oligodendrocytes (OD) able to repair myelin. However, in MS, this repair process fails , 30. Thiin vivo – indeed, NPC cells can be replaced by recombinant LIF alone.LIF naturally occurs in the CNS and is implicated in both primary myelination and remyelination. LIF is released by astrocytes during activity-dependent cross-talk between axons OPCs and OD, during normal myelination . It is kand demyelination in MS.In marked contrast to LIF, interleukin-17 (IL17) – the signature cytokine of inflammatory TH17 cells that are present in MS lesions – has adverse effects on myelination . Not onlA wide range of immunosuppressive treatment options are approved for the various types and stages of MS. These reduce the autoimmune attack and current disease modifyng therapies include beta-interferons, copaxone, fingolimid, nataluzimab and BG-12 (dimethyl fumarate). A recent addition is the monoclonal anti-CD52 antibody, alemtuzemab (previously known as CAMPATH-1H). However, all of these treatments have unwanted side effects. For alemtuzumab, secondary autoimmune disease is common. Alemtuzumab is a lymphodepleting antibody that spares bone marrow stem cells. In MS, it is used as part of a regimen of an induction therapy that first aims to deplete the entire immune system of the patient and, thereafter, allow the immune system to re-boot self-tolerance during homeostatic recovery. Initially, the patient is at high risk of infection. Thereafter, recovery is associated with significantly reduced disease. However, in a third of patients, secondary autoimmunities develop, most commonly of the thyroid. These appear to be driven by TH17 activity , 35, whein vivo, LIF-NP targeted to OPC increased the quality of myelin repair by both increasing numbers of remyelinated axons and increasing thickness of remyelinated axons. This proof of principle revealed two key points: (i) LIF that is delivered in the form of PLGA nanoparticles is bioactive within the brain . Given that the PLGA platform used for LIF-NP is the same as that used by BIND therapeutics , safety is unlikely to be an issue. This is especially the case, given the low dose of LIF and LIF's global reparative role at physiological levels. Considering the BBB, although this is defective in active MS lesions, sites that have become quiescent may be accessed by intranasal delivery. This is an optional delivery route that crosses the BBB at the cribiform plate at the back of the nasal cavity [But, a far more important role for LIF-NP in MS therapy is myelin repair, which is currently untreatable. Rittchen et al.  showed the brain  and (ii)l cavity  and has l cavity .As a treatment for MS, LIF has three values: (i) opposition of TH17 immunity, (ii) repair of demyelinated axons and (iii) promotion of self-sustaining self-tolerance to myelin . By treaWhen considering LIF-nanotherapy in terms of translation the clinic, the two immediate considerations are (i) route of delivery and (ii) de-risking. Firstly, route of delivery of LIF-NP is linked to the therapeutic aim. For modulating the immune response in autoimmune disease, systemic delivery to circulating lymphocytes via the intravenous route is one option. Alternatively, direct delivery to specific sites – for example, the inflamed joint – may be selected. For skin conditions, such as psoriasis, a topical formulation would be appropriate. For treatment within the CNS, the challenge of overcoming the BBB becomes less of an issue with the success of intra-nasal delivery. Here, nanoparticle-formulated cytokines and growth factors are highly relevant to the treatment of both neurodegenerative and demyelinating diseases, with advantages over the cell-based therapeutic approach. Nanomedicine delivering biologics is imminent, following on the heels of nano-based platforms for delivery of drugs that are currently in clinical trials.in vivo requires an understanding of the “deep” biology of the target and how this might be impacted by the candidate nanotherapeutic in holistic terms. The need for unifying expertise across the disciplines in order to maximize therapeutic gain, whilst avoiding any potential risk, is paramount. Such specialized de-risking will run alongside established de-risking strategies for a novel biologic therapeutic. For PLGA-based technology, approval by the FDA and the current clinical trials being run by BIND Therapeutics are encouraging.Secondly, in addition to standard pharmaceutical de-risking, safety is the central consideration for nanomedicine. As novel nanotherapeutic devices are developed, biocompatibility is crucial and biodegradation is a major advantage. This links to endogenous systems that can be harnessed by transient therapy, avoiding the potential of long-term physiological distortion due to the therapeutic . A combination of nanotechnology with biological systems The therapeutic potential of LIF enabled by formulation as PLGA nanoparticles extends to tolerogenesis ; support41Finally, the question arises – can LIF-NP act on an endogenous stem and precursor cells for tissue repair? This would provide a simple defined route to reduce or even replace the need for exogenous delivery of therapeutic stem cells in regenerative medicine.We dedicate this overview to Paul Patterson (1944–2014), who first recognized LIF's role in neuro-immunity and, more recently, identified maternal IL-6 as being linked to the risk of autism and schizophrenia in offspring, two amongst many of Paul's groundbring discoveries now being pursued worldwide.


P = 0.001). NMA revealed that most of the maintenance regimens containing new agents were significantly better than simple observation in terms of PFS but not OS. Len single agent was the most effective, considering PFS and OS both. We concluded that conventional maintenance has very limited effect. Maintenance containing new agents is highly effective in improving PFS, but has very limited effect on OS. Maintenance with Len may have the largest survival benefits. Emerging strategies may further change the landscape of maintenance of MM.We aimed to quantitatively synthesize data from randomized controlled trials (RCTs) concerning maintenance for multiple myeloma (MM). We searched electronic literature databases and conference proceedings to identify relevant RCTs. We selected eligible RCTs using predefined selection criteria. We conducted meta-analysis comparing maintenance containing new agents and conventional maintenance, and subgroup analysis by transplantation status and mainstay agent as well. We performed trial sequential analysis (TSA) to determine adequacy of sample size for overall and subgroup meta-analyses. We performed network meta-analysis (NMA) to compare and rank included regimens. A total of 22 RCTs involving 9,968 MM patients and 15 regimens were included, the overall quality of which was adequate. Significant heterogeneity was detected for progression-free survival (PFS) but not overall survival (OS). Meta-analyses showed that maintenance containing new agents significantly improved PFS but not OS , compared with controls. Subgroup analyses revealed lenalidomide (Len)-based therapies better than thalidomide-based ones (HR = 0.50 and 0.66, respectively;  Multiple myeloma (MM) is a common hematological malignancy that originates from plasma cells . TreatmeWe searched the PubMed, Embase, Cochrane collaboration database, and the proceedings of major international conferences in hematology and oncology to identify relevant RCTs. We used the following search terms: “MM,” “maintenance therapy,” and “randomized.” We also manually screened the reference lists of included studies and previous meta-analyses to find additional studies. Only publications in English were considered. The last search was performed on 30 May.We used the following criteria for inclusion eligibility: (i) the study subjects were patients with symptomatic MM, either newly diagnosed or previously treated; (ii) the design was RCT; (iii) different maintenance treatments (including Obs or Pla) were compared, with at least one arm containing new agents ; (iv) sufficient information was provided on PFS and/or OS. In case where data on PFS were not provided, data on event-free survival or time-to-progression were used as surrogates. Two investigators independently performed literature search and study selection. Any discrepancies were resolved by discussion with a third investigator.Two investigators independently extracted the following data from the included studies: name of the first author, year of publication, number of patients, agents used for maintenance, and ASCT status. The hazard ratio (HR) and corresponding 95% confidence interval (95%CI) of survival endpoints were either extracted directly from study reports or calculated from Kaplan–Meier curves as described previously . Any disTwo investigators independently assessed the methodological quality of included RCTs using the Cochrane collaboration’s risk-of-bias assessment tool . Any disI2 ≤ 50% and P-value of Q-test > 0.1, otherwise the random-effects model was used . Heterogeneity statistics were used to guide the choice of meta-analytic model. In brief, the fixed-effects model was used where the was used . Subgroug’s test . TSA wasg’s test . The a pg’s test . O’Briang’s test . Frequeng’s test . Obs/Plag’s test . The surg’s test . Clusterg’s test . All staFigure 1. 324 potentially relevant studies were retrieved by the initial search. 276 studies were excluded after title and abstract screening. Another 26 studies were excluded after full-text evaluation. Finally, 22 RCTs , and the pooled results by random-effects model showed that maintenance containing new agents significantly improved the PFS , as compared with controls. In contrast, no significant heterogeneity  was found for OS, and the improvement in OS was minimal and marginally non-significant , as compared with controls. Similar results were observed in subgroup analyses by ASCT status or mainstay agents . No significant difference between subtotals was observed except that Len-based therapies were associated with significantly larger benefits in PFS as compared with Tha-based therapies . Funnel plots for PFS was symmetric  but OS asymmetric , which indicated potential publication bias for OS.The forest plots of meta-analysis comparing maintenance containing new agents and conventional controls are illustrated in Supplementary Figure S3. For PFS, the cumulative Z-curves crossed the monitoring boundaries in overall and subgroup TSAs, indicating firm evidence of effect (true positive). In contrast, for OS, the cumulative Z-curves did not cross the monitoring boundaries with patients more than the required information size included, which indicated lack of effect (true negative), in all TSAs except the one focusing on the Len subgroup in which the required APDIS was not reached, which indicated absence of evidence of effects .The results of TSAs were shown in Supplementary Figure S4. Since no significant inconsistency detected (P > 0.05), the consistency model was used for the NMAs. The NMA results were presented in Table 2, with Obs/Pla as reference. For PFS, most of the maintenance regimens containing new agents were significantly better than Obs without active treatment. In contrast, for OS, no significant difference was noted between Obs and anyone of the other regimens. The SUCRA plots were illustrated in Supplementary Figure S5. Maintenance with Len and Pre was ranked first in terms of PFS, and maintenance with Tha and Pam was ranked first in terms of OS. Averaged mean rank and clustered ranking both showed that the maintenance with Len single agent was the most effective strategy, considering PFS and OS both, as presented in Supplementary Figure S6.A total of 14 maintenance strategies were included in the NMA. The network plots were shown in The main objective of maintenance treatment in MM patients is to prolong the duration of response and survival . In prevThe first agent ever used for MM maintenance is the interferon. The estimated potential mechanisms of interferon’s anti-MM effects as maintenance include the prolongation of cell cycle and overall generation time, G0/G1 blockage, inhibition of proliferation and self-renewal of MM cells, and immunomodulating effects. Although a few pilot studies reported that maintenance using interferon might increase duration of response and bring prognostic benefits to MM patients, recent reports revealed negative findings . The repP = 0.0534; Supplementary Figure S8). Based on this finding, it is suspected that the PFS may not be a good surrogate of OS in MM maintenance trials.Based on our meta-analyses and TSAs, it is very likely that maintenance therapies containing new agents can significantly improve patients’ PFS, compared with simple Obs or conventional maintenance, regardless of ASCT status and type of mainstay agents. However, maintenance therapies containing new agents have no beneficial effects on OS, regardless of ASCT status. Tha-based maintenance therapies bring no benefits in OS, and false-negativity may be present regarding the effect of Len-based maintenance on OS. The NMAs revealed similar findings. The conventional maintenance is no better than simple Obs, in terms of PFS and OS both, regardless of the agents used. Compared with Obs or Pla, the majority of maintenance therapies containing new agents significantly improved PFS, but none was associated with significant improvement in OS. Very interestingly, an obvious inconsistency between PFS and OS was observed in meta-analyses, TSAs and NMAs. As additional exploration, we performed a weighted (by sample size) least square linear regression to investigate the relationship between the logarithmic point estimates of HRs of PFS and OS, and we found that the correlation between PFS and OS were non-significant , histone deacetylase inhibitors  and monoclonal antibodies , including several RCTs. An updated NMA can be performed when their final results become available. The basic information of ongoing RCTs and the network map of the updated NMA are shown in I2 = 61%). After excluding this study from meta-analysis, the I2 dramatically decreased from 61 to 0%. Therefore, this study is probably an important source of heterogeneity. In addition, we speculate that the difference in induction regimen or ASCT protocols, risk-of-bias profile and duration of follow-up may also be potential sources of heterogeneity among trials. Second, potential risk of publication bias was indicated regarding OS meta-analysis. The trim-and-fill adjusted meta-analysis result is similar to the original one , indicating that the influence of potential risk of publication bias may be minor. Third, certain comparisons  in NMA were primarily based on indirect evidence, which had limited precision and power.The present study has certain limitations. First, significant heterogeneity was detected for PFS, which persisted in subgroupanalyses by ASCT status and mainstay drug. Interestingly, we noted that in the subgroup analyses by mainstay drug, there wasno significant heterogeneity among studies identified that the study by To summarize, the following conclusions are made: (i) conventional maintenance has very limited effect; (ii) maintenance containing new agents is highly effective in improving PFS, but has very limited effect on OS; (iii) maintenance with Len may have the largest survival benefits. In clinical practice, potential benefits, risks of adverse events, costs and patient’s preference should be considered and balanced for the choice of maintenance strategy. Emerging strategies may further change the landscape of maintenance of MM.X-YM designed and conceptualized the study. J-LL, G-YF, Y-JL, Z-HZ, J-JH, Z-MY, and X-YM participated in the literature search. J-LL and X-YM performed the data analysis. G-YF, Y-JL, and Z-HZ participated in quality assessment of the included studies. All authors participated in the reporting.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


RNAs play key roles in cells through the interactions with proteins known as the RNA-binding proteins (RBP) and their binding motifs enable crucial understanding of the post-transcriptional regulation of RNAs. How the RBPs correctly recognize the target RNAs and why they bind specific positions is still far from clear. Machine learning-based algorithms are widely acknowledged to be capable of speeding up this process. Although many automatic tools have been developed to predict the RNA-protein binding sites from the rapidly growing multi-resource data, e.g. sequence, structure, their domain specific features and formats have posed significant computational challenges. One of current difficulties is that the cross-source shared common knowledge is at a higher abstraction level beyond the observed data, resulting in a low efficiency of direct integration of observed data across domains. The other difficulty is how to interpret the prediction results. Existing approaches tend to terminate after outputting the potential discrete binding sites on the sequences, but how to assemble them into the meaningful binding motifs is a topic worth of further investigation.In viewing of these challenges, we propose a deep learning-based framework (iDeep) by using a novel hybrid convolutional neural network and deep belief network to predict the RBP interaction sites and motifs on RNAs. This new protocol is featured by transforming the original observed data into a high-level abstraction feature space using multiple layers of learning blocks, where the shared representations across different domains are integrated. To validate our iDeep method, we performed experiments on 31 large-scale CLIP-seq datasets, and our results show that by integrating multiple sources of data, the average AUC can be improved by 8% compared to the best single-source-based predictor; and through cross-domain knowledge integration at an abstraction level, it outperforms the state-of-the-art predictors by 6%. Besides the overall enhanced prediction performance, the convolutional neural network module embedded in iDeep is also able to automatically capture the interpretable binding motifs for RBPs. Large-scale experiments demonstrate that these mined binding motifs agree well with the experimentally verified results, suggesting iDeep is a promising approach in the real-world applications.http://www.csbio.sjtu.edu.cn/bioinf/iDeepThe iDeep framework not only can achieve promising performance than the state-of-the-art predictors, but also easily capture interpretable binding motifs. iDeep is available at The online version of this article (doi:10.1186/s12859-017-1561-8) contains supplementary material, which is available to authorized users. RNA-protein interactions are involved in many biological processes, such as gene regulation and splicing . DiscoveAlthough there are many genome-wide RNA-binding protein detection techniques, such as RNAcompete , PAR-CLIAt the very beginning of the methodology development of this field, predictors are mainly constructed by only using the sequence information. For instance, MatrixREDUCE simply fits a statistical mechanical model to infer the sequence-specific binding sites for transcription factors from sequences . DRIMustFeature-level fusion. This type of fusion strategy is to encode the different sources into feature vectors, which will be concatenated together. For instance, the OliMoSS model has integrated tetranucleotide sequence, binding motifs and secondary structures to predict protein specific interactions on RNAs by simply concatenating the different sources of features into one high-dimensional features (525-D) , which mDecision-level fusion. To solve the high-dimension space learning problem, decision level-based fusion system has been proposed. For instance, the iONMF  is a preBesides the high-throughput sequences, actually multiple sources of data are available from the genome-wide RNA-protein CLIP-seq data, such as sequences, structures, genomic context. Each source of data has a different kind of representation and correlation structure. A popular straightforward idea is to integrate these data to construct a predictor, which is expected to be very useful for enhancing the prediction accuracy. Two integration schemes have been widely used in the literatures: Despite the progresses of previously proposed methods, they have a shared drawback that the models were constructed on the features extracted from the observed data, where the frequent noise may make the subsequent classifiers learn wrong knowledge. Deep learning , 17 is aOne typical deep learning framework is known as the convolutional neural network (CNN) . The advThe deep belief network (DBN) is another deep learning algorithm to learn high-level features from large-scale data , which iIn this study, we propose a multimodal deep learning framework iDeep, a hybrid framework with CNNs and DBNs, to better integrate multiple heterogeneous data sources for predicting RBP interaction sites on RNAs Fig. . For theIn this study, we evaluated iDeep on independent testing datasets, and also compared it with the performance of DBN and CNN from individual sources of data. To demonstrate the advantage of iDeep, some state-of-art predictors of iONMF, DeepBind, and Oli were also compared. Besides, a large-scale analysis has been conducted to demonstrate the discovered binding motifs using iDeep.To demonstrate the ability of iDeep for predicting RNA-protein binding sites, we evaluate iDeep on independent testing dataset (see the dataset section). We firstly use 4000 training samples for model training, 1000 validation sites are evaluated at the end of each training epoch to monitor the convergence. For each experiment, iDeep is trained with the same initializations. After we obtain the trained model, we apply it to predict binding sites for 1000 independent testing samples. The ROC on 31 experiments are shown in Fig. We firstly compare it with state-of-the-art method iONMF, which has shown better performance than other existing methods , such asWe further compare iDeep with another protein-specific method Oli , which yTo demonstrate the merits of the designed framework of iDeep, we also compare iDeep with its own variant iDeep-kmer, whose input modalities are kmer, region type, clip-cobinding and structure using the same network architecture. The only difference is that iDeep uses CNN sequence and motif modalities instead of high-dimensional kmer modality. As indicated in Table Overall, compared to other 6 tested methods, iDeep yields the best performance on 18 of 31 experiments and the same AUCs on other 8 experiments. And it achieves a little lower AUC only on 5 of the 31 experiments, but it still yields the AUCs above 0.90 on 4 of them. For those experiments with AUCs below 0.90 in other six methods, iDeep’s performance is very encouraging. These results indicate that iDeep’s promising performance.To show the advantage of integrating multiple modalities of data, we also tested the performance on individual modalities. The average AUCs of 31 experiments for region type, clip-cobinding, structure, motif and CNN sequence are 0.73±0.11, 0.74±0.11, 0.71±0.12, 0.71±0.08 and 0.83±0.12, respectively, indicating that individual deep networks have the ability of learning high-level features for RBP binding sites prediction. From the results, we can see that CNN sequence modality yield the best average performance with roughly 12% improvement over the second most informative region type. And CNN sequence yields higher AUC on 22 experiments due to sequence specificities of binding RNA  centering the crosslinked sites is used to generate the feature vectors, which is the same as iONMF [It’s worth noting that since the iDeep model is constructed with the CNN algorithm, the 25856-D kmer and 39560-D GO features originally used in the iONMF are not used in our model. The main reasons are: 1) the GO features has been indicated of lower discriminating power than other sources of data [Convolutional Neural Network (CNN) is inspired by biological processes, it consists of one or more convolutional layers, followed by the max pooling layers. And it enforces a local connectivity pattern between neurons of layers to exploit spatially local structures. In this study, CNN is used to capture non-linear sequence features, e.g. motifs, and pull out some high-level features associated with RBP binding.Here RNA sequence is one-hot representation encoded into a 101 x 4 binary matrix, whose columns correspond to A, C, G and U , 19. TheDeep Belief Network (DBN) consists of multiple layers of Restricted Boltzmann machines (RBMs) , which lv∈{0,1} and hidden units h∈{0,1}. Its joint distribution of hidden and visible variables are defined as follows: Some of our extracted input features are binary, such as region type of nucleotides. RBM is developed for binary-valued inputs, which is a graphical model with visible E is defined: where vi and ai are binary state and bias for visible unit i, respectively. hj and bj are the binary states and bias for hidden unit j respectively.where The partition function Z is calculated by summing over hidden and visible variables, which is optimized using maximum likelihood estimation based on Contrastive Divergence algorithm . BesidesDBN is comprised of multiple RBMs, Here we take a DBN with two hidden layers as example: h(1) and h(2) are hidden units for two hidden layers, and W(1) and W(2) are weight parameters for visible-to-hidden and hidden-to-hidden connection.where DBN is able to capture high-level features from individual modalities, but it cannot interactively learn unified feature representations across them.Considering the heterogeneous representations of RBP binding sites, multimodal deep learning is developed to learn shared features across different sources of data . It consWe apply multimodal deep learning to integrate different sources of data to predict RNA-protein binding sites on RNAs. It first extracts different representations of different sources of data from CLIP-seq data, which are subsequently integrated using multimodal deep learning to predict RNA-protein binding sites. The flowchart is shown in Fig. In this study, we set the maximum number of epoch to 20, the batch size is 100. The neural network models are optimized using RMSprop algorithm  to learnhttps://github.com/fchollet/keras. The model architecture consists of hybrid CNNs and DBNs for individual inputs and additional layer for merging them.The iDeep is implemented in python using keras 1.0.4 library For sequence modality, its one-hot encoding is fed into CNN to learn high-level motif features. The parameter nb_filter (number of motifs) is 102. The size of the significantly verified RBP binding motifs in CISBP-RNA database is 7 and the 7-mer motifs can consistently score well . AccordiThe architecture of DBN for input modalities clip-cobinding, Structure, Region type and Motif consists of fully connected layer and dropout layers (Additional file There are many computational methods developed for predicting RNA-protein binding sites. such as iONMF, Oli, DeepBind, GraphProt and RNAContext. As indicated in , iONMF p


Migraine is frequently comorbid with restless legs syndrome (RLS), both displaying functional connectivity (FC) alterations in multiple brain networks, although the neurological basis of this association is unknown.We performed resting-state functional magnetic resonance imaging and network-wise analysis of FC in migraine patients with and without RLS and healthy controls (CRL). Network-based statistics (NBS) and composite FC matrix analyses were performed to identify the patterns of FC changes. Correlation analyses were performed to identify associations between alterations in FC and clinical profiles.NBS results revealed that both migraine patients with and without RLS exhibited lower FC than CRL in the dorsal attention, salience, default mode, cingulo-opercular, visual, frontoparietal, auditory, and sensory/somatomotor networks. Further composite FC matrix analyses revealed differences in FC of the salience, default mode to subcortical and frontoparietal, auditory to salience, and memory retrieval networks between migraine patients with and without RLS. There was a trend toward a negative association between RLS severity and cross-network abnormalities in the default mode to subcortical network.Migraine patients with and without RLS exhibit disruptions of brain FC. Such findings suggest that these disorders are associated with differential neuropathological mechanisms and may aid in the future development of neuroimaging-driven biomarkers for these conditions. Migraine is a primary headache disorder affecting 10–20% of the general population, which occurs predominantly in women . It is characterized by recurrent headaches associated with moderate-to-severe pulsating pain and sensory hypersensitivity . RLS is via pairwise coupling, which may fail to elucidate the role of such connections within the greater network. Moreover, these methods do not provide insight into how migraine with or without RLS (MIG w or w/o RLS) is associated with the restructuring of functional networks, particularly at the connectome level. In contrast, network-based statistics (NBS) provide a general framework for the characterization of specific network components, which may help identify whether and which subnetworks exhibit significant functional differences between patients with MIG w or w/o RLS  brain FC is altered in migraine patients with or without RLS when compared to controls; (2) migraine patients with or without RLS show changes in FC patterns; and (3) changes in FC correlate with clinical variables.The present study was approved by the Ethics Committee of Taipei Veterans General Hospital (TVGH) and Tri-Service General Hospital (TSGH) in Taiwan. All methods were carried out in accordance with the approved guidelines. All participants signed a written informed consent form after a full written and verbal explanation of the study. Patients with episodic migraine were recruited from the Headache Clinic at TVGH and TSGH. All participants met the diagnostic criteria for episodic migraine based on the third edition of the International Classification of Headache Disorders . None haAll patients underwent a detailed history, physical examination, laboratory testing, and electromyography to exclude secondary forms of RLS. No patients had a history of psychiatric symptoms, and none were treated with psychotropic medications, except for two patients with MIG w RLS taking a dopaminergic agent (ropinirole). Other clinical data such as sex, age, duration of RLS, duration of migraine, and sleep quality were recorded. RLS severity was assessed using the IRLSSG rating scale . PatientThe healthy control (CRL) group was composed of volunteers without RLS or migraine matched for age, sex, and handedness. Control participants were recruited through community advertisements and hospital patient pools. Exclusion criteria for control participants included a family history of RLS or migraine, prior diagnosis of a primary or secondary headache disorder, and any chronic pain condition. Statistical analysis of demographic data was performed using SPSS software version 20 . Our study included 22 patients with migraine without idiopathic RLS  and 22 patients with migraine with idiopathic RLS . The control group was composed of 19 age- and sex-matched adults  with no history of neurologic or psychiatric disease.All images were collected at TVGH using a 3T MRI scanner  equipped with an eight-channel phase array head coil. A whole-brain axial T1-weighted anatomical scan was acquired using a three-dimensional inversion recovery prepared fast spoiled gradient recalled sequence . Whole-brain spontaneous activity was measured using a T2*-weighted blood oxygenation level-dependent contrast-sensitive gradient-echo echo-planar imaging sequence . Two-hundred image volumes were acquired for each participant. During the rs-fMRI acquisition, the participants were instructed to remain relaxed and awake with their eyes closed. An experienced radiologist evaluated each brain anatomical scan for gross abnormalities.Data preprocessing was conducted using AFNI . According to the FD exclusion criteria, subjects with the following two conditions were acceptable to be further excluded: (1) mean FD was larger than 0.25 mm, and (2) over 40% of the image volume was removed after censoring all time points with FDs > 0.25 mm . Combinir-to-z transformation was used to improve the normality of the correlation estimates. Then, the unthresholded FC matrices  were used for further network-level analysis.The analytical steps of the present study are summarized in Figure t > 4, p < 5 × 10−4, one-tailed) was first applied to identify a set of suprathreshold edges, at which time all connected components and their sizes were determined. Five-thousand permutations were then used to generate the empirical null distribution for the size of the largest connected component and to estimate the significance of each identified component. Only components whose size exceeded the family-wise error (FWE)-corrected p-value of <0.05 were deemed to be statistically significant. Participant age, sex, and mean FD were regarded as nuisance variables. Since NBS results are highly dependent on the initial cluster-defining threshold, we performed an additional series of NBS analyses with different initial cluster-defining thresholds -corrected p-value of <0.05. We further performed a conjunction analysis to identify the shared intra- and interconnectivity changes in functional subsystems in each patient group. This analysis was performed by searching for the union-section of the FDR-thresholded matrices from patient–control comparisons  were used to identify associations between the strengths of abnormal connections and clinical variables . Only connections identified using composite FC matrix analysis for both patient groups were included for correlation analyses.p = 0.89) or age (p = 0.92) between patients and control participants. Demographic and clinical characteristics are summarized in Table p = 0.88).There were no significant differences in sex (PFWE-corrected = 0.027), in the network composed of the dorsal attention, salience, default mode, visual, and frontoparietal networks , in the network composed of the default mode, cingulo-opercular, auditory, and sensory/somatomotor networks  in patients with MIG w RLS.There was a trend for a negative association between cross-network abnormalities in the default mode to subcortical network and RLS severity as assessed using the IRLSSG  with regard to the salience, default mode to subcortical and frontoparietal, salience to auditory, and memory retrieval networks. Most of the observed changes were associated with attentional modulation, sensory, anti-nociception, and limbic networks. Furthermore, it has been reported that children with both migraine and periodic limb movement disorders (including RLS) may have more severe migraine clinical presentation, severity, frequency, and other disabling aspects than children with migraine without periodic limb movement disorder . TherefoFurthermore, among the patients with RLS, the IRLSSG severity score exhibited a trend-level significance for a negative association with cross-network abnormalities between the default mode and subcortical networks. Weaker connection between these two networks may be associated with higher RLS severity. Migraine is phenotypically different from RLS, as it is characterized by a prominent worsening of symptoms during physical movement. As a result, patients with migraine avoid movement during attacks. In contrast, motor restlessness can only be relieved by voluntary movement in patients with RLS . Such fiIn the present study, we identified the patterns of FC changes in patients with MIG w and w/o RLS. Our findings may aid in the development of neuroimaging-driven biomarkers in future studies. However, the present study possesses some limitations of note. First, the data in this study were obtained using a cross-sectional design. Thus, further longitudinal studies are required to determine whether the functional alterations are dynamic. Second, since most brain networks exhibiting an alteration in the present study are associated with higher cortical function, future studies should employ comprehensive cognitive testing to evaluate the relationships between these brain network alterations and cognition. Third, our sample size was not very large; however, we used a strict definition for diagnosis to ensure high quality of our investigation. Fourth, migraine prevalence peaks between the ages of 20 and 40 years, whereas RLS prevalence peaks after the age of 50 years , 5, 10. In conclusion, we observed disrupted FC in patients with MIG w and w/o RLS when compared to CRL. Both groups displayed a common pattern of FC changes that predominantly affected sensorimotor and attention-related networks. The two groups exhibited FC changes most prominently in the attentional nociceptive control and sensory-related networks. Certain functional network metrics also exhibited a trend-level significance for correlation with RLS severity. Thus, our findings may aid in the development of potential connectome-based biomarkers for MIG w and w/o RLS.The present study was approved by the Ethics Committee of TVGH and TSGH in Taiwan. All methods were carried out in accordance with the approved guidelines. All participants signed a written informed consent form after a full written and verbal explanation of the study.F-CY, K-HC, A-LH, and SJW participated in data collection, analyzed the data, and drafted the manuscript. F-CY, K-HC, A-LH, J-LF, J-FL, H-WK, C-PL, and S-JW participated in the study design, collected the data, and helped to draft the manuscript. C-PL and S-JW supervised the study, conceptualized and designed the study, and helped to draft the manuscript. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Multi-drug-resistant tuberculosis (MDR-TB) has emerged as a challenge to global tuberculosis (TB) control and remains a major public health concern in many countries. Diabetes mellitus (DM) is an increasingly recognized comorbidity that can both accelerate TB disease and complicate its treatment. The aim of this study is to summarize available evidence on the association of DM and MDR-TB among TB patients and to provide a pooled estimate of risks.2 statistic. We will check potential publication bias by visual inspection of the funnel plot and Egger’s regression test statistic. We will use the random effects model to compute a pooled estimate.All studies published in English before October 2016 will be searched using comprehensive search strings through PubMed, EMBASE, Web of Science, and WHO Global Health Library databases which have reported the association of DM and MDR-TB in adults with TB (age > =15). Two authors will independently collect detailed information using structured data abstraction form. The quality of studies will be checked using Newcastle-Ottawa Scale for cohort and case-control studies and the Agency for Healthcare Research and Quality tool for cross-sectional studies. Heterogeneity between included studies will be assessed using the IIncreases in the burden of non-communicable diseases and aging populations are changing the importance of different risk factors for TB, and the profile of comorbidities and clinical challenges for people with TB. Although classic risk factors and comorbidities such as overcrowding, under-nutrition, silicosis, and HIV infection are crucial to address, chronic conditions like diabetes are important factors that impair host defenses against TB. Thus, undertaking integrated multifaceted approach is remarkably necessary for reducing the burden of DM and successful TB treatment outcome.CRD42016045692.PROSPERO The online version of this article (doi:10.1186/s13643-017-0407-9) contains supplementary material, which is available to authorized users. Multi-drug-resistant tuberculosis (MDR-TB) has emerged as a challenge to global tuberculosis (TB) control and remains a major public health concern in many countries. It is an infectious disease caused by strains of mycobacterium TB that are resistant to at least isoniazid and rifampicin . Drug-reIn the year 2014, an estimated 3.3% of new cases and 20% of previously treated TB cases have MDR-TB [The emergence of multi-drug resistance across the world poses a global threat as the treatment is difficult, expensive, and a major health care cost burden to developing countries . Most caDiabetes mellitus (DM) is an increasingly recognized comorbidity that can both accelerate TB disease and complicate TB treatment. The prevalence of DM among TB patients around the world varies according to different regions that range from 12 to 44% and tended to increase in the past decade . It incrSimilarly, none of the systematic reviews and meta-analysis conducted so far , 30–36 hhttp://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42016045692; registration number CRD42016045692). This protocol is written in accordance with recommendations from the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) 2015 statement [Our systematic review has been registered with the International Prospective Register of Systematic Reviews (PROSPERO)  which have reported the association of DM and MDR-TB in adults with TB (age > =15). All studies published in English before October 2016 will be reviewed as well.PubMed, Excerpta Medica Database(EMBASE), Web of Science, and WHO Global Health Library databases will be searched for all publications. We will also search bibliographies of identified articles and gray literature. In addition, authors will be contacted and requested for additional information in case of missing data. In consultation with an experienced medical information specialist, comprehensive search strategy has been developed  they provided or permitted the computation of an effect estimate of DM on the development of MDR-TB among TB patients. (2) They included TB patients  and defined MDR-TB based on standard protocols. (3) They defined DM as any of the following: baseline diagnosis by self-report, medical records, laboratory test, or treatment with oral hypoglycemic medications or insulin. We will exclude studies for any of the following reasons: citations without abstracts; anonymous reports; duplicate studies; case reports or studies which did not compare MDR-TB among people with DM to people without DM; systematic reviews and meta-analysis. Also, studies in which people with DM received different anti-TB treatment regimens than people without DM and studies that either did not provide effect estimates in odds ratios, rate ratios, hazard ratios, or relative risks or did not allow for the computation of these values will be excluded. Two reviewers will screen and check full-text studies for inclusion independently. Any disagreements will be resolved by discussion between the two reviewers. If consensus could not be reached, a third reviewer will determine the eligibility and approve the final list of retained studies.http://www.refworks.com). The same authors (BS and TD) will check the quality of studies independently using Newcastle-Ottawa Scale (NOS) [Structured data abstraction form will be constructed and pre-tested. For every study that met our eligibility criteria, two investigators (BS and TD) independently will extract the title, name of authors, year of publication, country, study design, study population, sample size, data collection procedure, diagnosis of DM, and MDR-TB, adjustment for potential confounders, effect sizes with 95% confidence intervals and proportion of TB-diabetic patients who developed MDR. Search results will be compiled using citation management software   for cohole (NOS)  tool for2 statistic described by Higgins et al. with I2 from 75 to 100% suggesting considerable heterogeneity [P value less than 0.10.Review Manager (RevMan) version 5.3.5 (Cochrane Informatics and Knowledge Management Department) for Windows  will be ogeneity .We will ogeneity . PublicaOriginal studies will be described using study characteristics summary table and forest plot. A meta-analysis, to compute a pooled estimate, will be performed if variability among studies is low. However, if the pooling of data is not feasible due to heterogeneity, we will descriptively report the results of each study. Odds ratio will be used as a measure of overall association between DM and MDR-TB. We will meta-analyze estimates with similar sets of confounds. Presuming the variation of the true effect of DM on MDR-TB for different populations, we will use the random effects model and weighting method . SubgrouIncreases in the burden of non-communicable diseases and aging populations are changing the importance of different risk factors for TB. Although classic risk factors and comorbidities such as overcrowding, undernutrition, silicosis, and HIV infection are crucial to address, chronic conditions like diabetes are important factors that impair host defenses against TB .The association of diabetes and TB was confirmed by Root since 1934 . So far,Clinicians and researchers should generate the necessary evidence for improvements to patient services and policies on combined TB and diabetes . Our rev


Several studies suggest that alternatives to carbapenems, and particulary beta-lactam/beta-lactamase inhibitor combinations, can be used for therapy of extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE)-related infections in non-ICU patients. Little is known concerning ICU patients in whom achieving the desired plasmatic pharmacokinetic/pharmacodynamic (PK/PD) target may be difficult. Also, in vitro susceptibility to beta-lactamase inhibitors might not translate into clinical efficacy. We reviewed the recent clinical studies examining the use of BL/BLI as alternatives to carbapenems for therapy of bloodstream infection, PK/PD data and discuss potential ecological benefit from avoiding the use of carbapenems. With the lack of prospective randomized studies, treating ICU patients with ESBL-PE-related infections using piperacillin–tazobactam should be done with caution. Current data suggest that BL/BLI empirical use should be avoided for therapy of ESBL-PE-related infection. Also, definitive therapy should be reserved to patients in clinical stable condition, after microbial documentation and results of susceptibility tests. Optimization of administration and higher dosage should be used in order to reach pharmacological targets. Since the 1980s, extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae (ESBL-PE) have been spreading worldwide . Several To reduce the ecological risk associated with the increased consumption of last-line antibiotics, two main strategies are available: (1) searching for alternative treatments for ESBL-PE-related infections and (2) antimicrobial de-escalation (ADE). Therefore, the use of alternatives to carbapenems such as cephamycins, piperacillin–tazobactam and others for the treatment of ESBL-PE infections should be investigated. A recent systematic review, including two randomized controlled trials and 12 cohort studies, highlighted that the effects of ADE on antimicrobial resistance have not been properly studied . HoweverUntil recently, the common rule is to treat infections caused by ESBL-producing organism with carbapenems. However, ESBLs are inhibited in vitro by beta-lactamase inhibitors and several studies have suggested the use of β-lactam/β-lactamase inhibitor combinations (BL/BLIs) such as piperacillin–tazobactam as a carbapenem-sparing strategy for the treatment of ESBL-PE-related infections –13. The While several studies are conducted in ICU, data remain scarce concerning other beta-lactams in non-ICU- , 17 and In critically ill patients, pharmacokinetics of beta-lactam antibiotics differs from healthy volunteers. Lower than expected concentrations have been reported for meropenem, piperacillin, amoxicillin, as well as for cephalosporins –26. BesiThis narrative review, based on microbiological, pharmacodynamics, clinical and ecological data, describes the available evidence for the use of Pip–Taz as an alternative to carbapenems in critically ill patients and to provide some guidance to prescribers for using these drugs when treating infections caused by ESBL-PE.A literature search was performed via PubMed, including all records from 1990 through April 2016. The following search pattern was applied: (ESBL OR extended-spectrum β-lactamases) AND (infection) AND . Reference lists were cross-checked to identify further publications for possible inclusion. We restricted inclusion to studies published in the English, Spanish and French languages.We screened and included studies in three categories according to the following criteria: (1) pharmacokinetics and pharmacodynamics studies, where all studies investigating the PK/PD of the potential alternatives to carbapenems in ICU patients were included. (2) For clinical studies, we restricted inclusion to studies reporting mortality of patients receiving empirical or definitive treatment with a non-carbapenem therapy for an ESBL bacteremia in adult patients. Patients with community-, hospital- and healthcare-associated bacteremia were eligible for inclusion. (3) Finally, considering ecological studies, we included any published article reporting carbapenem-resistant Enterobacteriaceae (CRE). Among the eligible articles, studies were included if they reported on exposure to any previous antibiotic class as a risk factor associated with CRE acquisition.E. coli is usually regarded as more susceptible to all beta-lactams than ESBL-producing K. pneumoniae, piperacillin–tazobactam (Pip–Taz) being the most effective antibiotic . Thus, BL/BLIs may lead a poorer outcome than carbapenem therapy for critically ill patients with ESBL-PE infection from non-urinary sources.Among studies including ICU patients, 6 (56%) compared BL/BLIs to carbapenems as empirical therapy. However, BL/BLIs was the only alternative compared to carbapenems in only 3 studies , 20, 51.ne study , 51. HowFinally 7/11 (63%) studies compared BL/BLIs to carbapenems as definitive therapy, of which 4 (36.3%) compared BL/BLIs as the only alternative to carbapenems , 22, 51.While initial research suggested the relative safety of imipenem–cilastatin on the intestinal microbiota , the recKlebsiella pneumoniae.The effect of non-carbapenem antibiotics on the emergence of multidrug-resistant bacteria and specifically carbapenem resistance is a major issue. In animal models, imipenem–cilastatin had no effect on the indigenous microflora . In a moWhether carbapenem is the only antibiotic class associated with the selection of carbapenem-resistant gram-negative isolates is an important issue, especially regarding the worldwide spread of carbapenemase-producing Enterobacteriaceae (CPE). These data suggest that antibiotics that disturb the intestinal anaerobic microflora and lack significant activity against KPC-Kp may promote colonization by this organism  Table 33.Table 3In our review of BL/BLI for the treatment of ESBL-PE, we found that they may be an alternative to carbapenems in a selected number of cases, based on antibiogram and CMI data, and always with pk/pd optimization.The use of alternatives for empirical therapy in suspected ESBL-related infections is usually limited by the level of resistance , the risThe efficacy of Pip/Taz antibiotics on ESBL-PE depends on the variety and amount of enzyme produced by the isolates Table . OverallE. coli species [In the absence of a well-designed prospective randomized study comparing carbapenems to non-carbapenems in ICU patients infected with ESBL-PE, we must rely on the evidence provided by observational data. Observational studies considering the empirical treatment of ESBL-related infections with BL/BLIs have infrequently included ICU patients  and more species . Althoug species , 51, 69, species , 20.Furthermore, when analyzing those publications with a focus on the use of alternatives to carbapenems for definitive therapy, a number of limitations hamper the interpretation of studies comparing BL/BLI to carbapenems.Firstly most of these studies were not designed to compare different antibiotic strategies. Secondly, the authors did not take into account the severity of underlying diseases, delays to antimicrobial treatment and effectiveness source control, which are all major predictors of outcome . ThirdlyEscherichia coli and did not account for the impact of MICs and pharmacodynamics data. The impact of MIC seems to be crucial for therapeutic efficacy when using alternatives to carbapenems as the cornerstone of treatment. Several studies [Fourthly, most of the studies included infections related to ESBL-producing  studies  emphasiz studies . However studies  the prob studies . Also itThere are now enough published data on the pk/pd of piperacillin/tazobactam to recommend the use of high daily doses and prolonged infusion ICU patients and in all cases of difficult to treat pathogens such as ESBL-PE.Pseudomonas aeruginosa resistance to imipenem and meropenem [The ecological consequences of a given antibiotic class depend on the amount of drug reaching the different microbiota. The net result depends on both the antibiotic concentrations achieved and the susceptibility of bacterial species in the microbiota. All antibiotics alter the composition, diversity and density of the microbiota and select for antibiotic resistance . The “eceropenem , 53. Howeropenem  and animeropenem  suggesteeropenem , 62, anderopenem . Our reveropenem , 79–92. One of the limitations of our study lies in the fact that we did not mentioned the two recent BL/BLIs approved by FDA and EMA, ceftolozane–tazobactam and ceftazidime–avibactam which are active in vitro against ESBL-producing Enterobacteriaceae. Several recent studies highlighted the in vitro efficacy of these two antibiotics on ESBL-producing Enterobacteriaceae , 93. AlsA definitive answer to the question addressed in this review would need a randomized study conducted in ICU, including severe infections related to ESBL-PE. Cases should be selected according to the results of antibiotic susceptibility tests, and the trial should compare carbapenems to BL/BLI as definitive therapy. Pending such a trial, piperacillin–tazobactam should be used with caution for treatment of ESBL-PE-related infections. In ICU patients, empirical use should be avoided, and definitive therapy should be reserved to patients in clinical stable condition, after microbial documentation and results of susceptibility tests, together with adapting the administered dose and modalities of infusion to the MIC of the infecting microorganism in order to reach pharmacological targets.


Obesity now affects millions of people and places them at risk of developing metabolic syndrome, nonalcoholic fatty liver disease (NAFLD), and even hepatocellular carcinoma. This rapidly emerging epidemic has led to a search for cost-effective methods to prevent the metabolic syndrome and NAFLD as well as the progression of NAFLD to cirrhosis and hepatocellular carcinoma. In murine models, time-restricted feeding resets the hepatic circadian clock and enhances transcription of key metabolic regulators of glucose and lipid homeostasis. Studies of the effect of dawn-to-sunset Ramadan fasting, which is akin to time-restricted feeding model, have also identified significant improvement in body mass index, serum lipid profiles, and oxidative stress parameters. Based on the findings of studies conducted on human subjects, dawn-to-sunset fasting has the potential to be a cost-effective intervention for obesity, metabolic syndrome, and NAFLD. Obesityl weight , which fl weight . The ramThe Third National Health and Nutrition Examination Survey conducted between 1988 and 1994 reported that ~20% of the U.S. population had NAFLD . It has Escherichia) and Verrucomicrobia (Akkermansia) and suggest that gut microbiota indirectly contribute to reduced host weight and recurrent adiposity [Changes in diet and exercise are the mainstay preventative approaches for NAFLD. However, the majority of obese patients are unable to accomplish or sustain intentional weight reduction by diet and exercise alone . Medicaldiposity . Numeroudiposity , 22 and diposity .Over the last two decades, human and animal studies have shown that timing of meal intake is as important as the composition of the diet and caloric quantity to prevent obesity and its complications –33. MealIt has been suggested that time-restricted food intake might be a successful intervention to prevent and manage obesity, metabolic syndrome, and its complications due to neurohormonal adaptions –33. AlteMicronutrient availability promotes cellular growth and proliferation through various inductive mechanisms, such as amino acid sensing and reactive activation of the mechanistic mammalian target of rapamycin complex 1, the central metabolic regulator . The indCentrally, the suprachiasmatic nucleus (SCN) of the hypothalamus hosts a molecular clock that serves as the driving force for circadian rhythmicity , 45 and The hepatic biological clock can be set or reset by two major mechanisms, light and mealtime , 52–56. A secondary hepatic clock mechanism functions in response to time-restricted feeding that releases the hepatic clock from the control of the master clock in the SCN , 53, 55.α, and Cyp2a5. In summary, several murine studies showed that time-restricted feeding during light phase under 12-hour light/12-hour dark cycle or during subjective light phase under 24-hour constant darkness for at least several days resets the phase of hepatic clock [In contrast to humans, most food consumption and activity in mice occur during night time (dark phase) , 59, 60.ic clock , 59, 60 ic clock , 53, 55.α, Cry1, Clock, Rorα, and Dbp when compared to mice on high-fat diet ad libitum. Hara et al. [Hatori et al.  showed ta et al.  showed ta et al. . Collecta et al. , Hara eta et al. , and Shea et al.  suggest Results of several murine studies showed that timing to food access, in the fasting state, is the cue “Zeitgeber” to entrain hepatic oscillators –55, 59 aα mRNA), reduced inflammatory markers , and reduced serum cholesterol and triglyceride levels compared to mice fed ad libitum. Average food intake to total body mass ratio in time-restricted and ad libitum feeding groups were almost the same [Sherman et al.  showed tthe same . The resthe same , 59, 60.the same  showed tthe same . That stthe same , showed the same . Short dthe same .−/−) mice fed only at night time had about 25% increase in hepatic triglyceride levels compared to clock-disrupted mice fed ad libitum [Adamovich et al.  showed t libitum . Interes libitum . The res libitum .Several key regulators of glucose and lipid homeostasis have a circadian rhythm set by light-dark cycles and feeding times , 63–65. Enterobacter aerogenes, a habitant of the human gut, showed swarming activity and motility in the culture that corresponded to host circadian clock oscillations and was melatonin dose- and temperature-dependent (melatonin effect on gut microbiome) [The effect of fasting and feeding patterns on metabolism can be closely associated with alterations in gut microbiota. Zarrinpar et al.  and Thairobiome) . Taken arobiome) , 69, androbiome) –73, enterobiome) , or foodrobiome) , 78 melarobiome) . Howeverβ-diversity, reduced obesity-associated Lactococcus species and significantly increased obesity-protective Ruminococcaceae compared to mice fed with high-fat diet ad libitum under 12-hour light/12-hour dark cycle for 8 weeks. If time-restricted feeding can prevent obesity and complications [Several studies have linked obesity and metabolic syndrome to alterations in the gut microbiome –89. The ications  and exerications  in murinconsecutive rhythmic dawn-to-sunset fasting for a month that has been practiced for over 1400 years “The Noble QUR'AN, Surah Al-Baqarah (Surah 2: Verse 187)”. The fasting without eating or drinking starts at civil dawn after a predawn breakfast and ends at sunset with a dinner. There are several spiritual meanings associated with Ramadan, including teaching self-discipline and healthy survival practices, attributes typically lacking among the obese. It is unclear what biological factors prompt the most favorable changes toward health, but evidence points to stool microbiota as a key factor, possibly working in concert with circadian rhythm by increasing the melatonin expression in the gut. Ramadan fasting is a type of time-restricted feeding model without any calorie restriction, and only lunch and snacks between breakfast and dinner are skipped. In murine models, time-restricted feeding for several days resets (regulates) the phase of hepatic circadian rhythm [Ramadan fasting is a convenient model of n rhythm –55. Thisn rhythm , 59, 60.n rhythm .When conducting fasting studies, the distinction between dawn and sunrise is crucial because significant metabolic and hormonal changes in humans start at dawn, not at sunrise . The impA study conducted on eight healthy subjects who fasted from dawn-to-sunset showed that acrophase (time at which the amplitude of the circadian rhythm peaks) of the rectal temperature on the 25th day of fasting shifted lagging for 2 to 3 hours (delayed) compared to acrophase detected 15 days before the initiation of fasting . In anotIt is unknown whether dawn-to-sunset fasting also results in uncoupling of the hepatic clock from the master clock in SCN , 53, 55 Many studies have shown that significant weight loss occurs during dawn-to-sunset Ramadan fasting  24, 28––28–32 buP < 0.001) [Lipid profiles were also shown to improve in a study by Temizhan et al.  of 52 su< 0.001) . TherefoThere were also studies that showed conflicting findings  25, 28,,28, 32. Mathew et al.  performeFor the effects of dawn-to-sunset fasting on hypertension and diabetes, several studies have shown encouraging results. We identified two studies that reported significant improvement in blood pressure in subjects with cardiovascular disease , 29. A gA well-designed rigorous study conducted on 32 healthy men showed significant improvement in fasting blood glucose levels measured at the 29th day of dawn-to-sunset fasting compared to prefasting levels . One genAksungar et al.  reportedResults of two studies performed in normal controls, hypertensive, and diabetic subjects showed significant improvement in oxidative stress parameters including increased blood glutathione and reduced serum malondialdehyde levels at the 4th week of dawn-to-sunset fasting , 27. RemSeveral studies have shown that the dawn-to-sunset Ramadan fasting could be unfavorable for health –103, butDawn-to-sunset Ramadan fasting starts at dawn and ends at sunset. Therefore, fasters have two major meals a day, breakfast before dawn and dinner after sunset. They can eat ad libitum from sunset until dawn. In general, it is a common practice for Ramadan fasters to work and fast during the daytime, have a dinner, sleep, and wake up one hour before dawn to eat and restart fasting at dawn. Most of the aforementioned studies did not provide sufficient dietary information on meal content, frequency of meals between sunset and dawn, and sleeping times. Furthermore, subjects might be compelled to secretly break the fast and further confound the desired adaptive response. There was no information on the compliance monitoring with fasting in any of the studies. Well-designed clinical trials that will evaluate the impact of dawn-to-sunset fasting on BMI and key metabolic parameters before, during, and after fasting should bring important health maintenance information.The long-term health benefits of dawn-to-sunset fasting have not yet been appreciated, but the data support the prospect of favorable outcomes. Individuals with certain medical conditions  should check with their physicians before they fast , 106. Diβ levels and had a significant increase in adiponectin levels compared to the normal diet group [There are few human fasting models other than dawn-to-sunset Ramadan fasting in which the caloric reduction was not the goal. Moro et al.  randomizet group .In a study conducted by Halberg et al. , eight hWe anticipate that consecutive rhythmic dawn-to-sunset fasting might be a cost-effective intervention to prevent obesity, metabolic syndrome, NAFLD, cirrhosis, and hepatocellular carcinoma if definitely shown to be advantageous, and further studies are needed. The challenge to implementing such a fasting routing would be compliance and lifestyle changes to facilitate such a radical intervention. Future studies should not only focus on short-term effects of dawn-to-sunset fasting  but also on longer lasting effects  as well as study the metabolic memory that one can sustain following a period of dawn-to-sunset fasting.


Over the last decade, a growing body of studies regarding the application of eHealth and various digital interventions has been published and are widely used in the psycho-oncological care. However, the effectiveness of eHealth applications in psycho-oncological care is still questioned due to missing considerations regarding evidence-based studies on the demands and needs in cancer-affected patients.This cross-sectional study aimed to explore the cancer-affected women’s needs and wishes for psycho-oncological content topics in eHealth applications and whether women with cancer differ in their content topics and eHealth preferences regarding their experienced psychological burden.Patients were recruited via an electronic online survey through social media, special patient Internet platforms, and patient networks . Participant demographics, preferences for eHealth and psycho-oncological content topics, and their experienced psychological burden of distress, quality of life, and need for psychosocial support were evaluated.Of the 1172 patients who responded, 716 were included in the study. The highest preference for psycho-oncological content topics reached anxiety, ability to cope, quality of life, depressive feelings, and adjustment toward a new life situation. eHealth applications such as Web-based applications, websites, blogs, info email, and consultation hotline were considered to be suitable to convey these content topics. Psychological burden did not influence the preference rates according to psycho-oncological content and eHealth applications.Psycho-oncological eHealth applications may be very beneficial for women with cancer, especially when they address psycho-oncological content topics like anxiety, ability to cope, depressive feelings, self-esteem, or adjustment to a new life situation. The findings of this study indicate that psycho-oncological eHealth applications are a promising medium to improve the psychosocial care and enhance individual disease management and engagement among women with cancer. Breast and gynecological cancer and the treatment of these diseases are psychologically challenging for affected women. A variety of physical and psychosocial impairments and lifestyle changes can occur and result in a lower health-related quality of life (QoL) and higher unmet supportive care needs -3. As a Due to the high cancer-related psychological burden, current international and national cancer guidelines recommend early assessment of and support for psychosocial problems, distress, unmet supportive care needs, problems with daily activities, and lifestyle risks ,15. TherA variety of psycho-oncology interventions have been developed to support cancer-affected patients during and after treatment to reduce unmet supportive care needs -20. HoweThe aims of this cross-sectional study were to describe the cancer-affected women’s needs and demands for psycho-oncological content topics for eHealth applications and determine if women with cancer differ in their demands regarding their experienced psychological burden .A total of 1172 women with either breast or gynecologic cancer (or both) were assessed in a cross-sectional approach. Patients were recruited to answer an electronic online survey (Questback) through social media, special patient Internet platforms, self-help group leaders, patient networks , and cancer counseling centers. Duplicate entries were avoided by preventing users with the same IP address further access after completion of the survey. Furthermore, consecutive inpatients and outpatients were asked whether they would like to participate in the study . The self-reported paper-and-pencil or self-reported online questionnaires took participants an average of 20 minutes to complete. Eligibility criteria were defined as an adult (age 18 years and older) with breast cancer, gynecologic cancer, or both with sufficient language skills to complete a set of questionnaires. Participation was voluntary and anonymous; no personal identifying information was collected from the patients. The beginning of the questionnaire included the consenting page. Of the 1172 participants assessed, 41 did not meet the eligibility criteria because of another cancer diagnosis. Incomplete datasets (less than 80% response rate) were excluded, resulting in a final dataset of 716 participants, with 581 surveys completed online and 135 surveys completed as paper-and-pencil questionnaires. The local ethics committee of the University Hospital Tuebingen approved the study protocol.Demographic variables included age, gender, marital status, and number and age of children. Self-reported data on the type of cancer, time since primary diagnosis, and status of disease  were also collected.The patient preference survey was self-generated. In total, 25 items considered the patient preference items for an ePOA. Two categories were created with 19 content topics for a psycho-oncological intervention and 6 possible eHealth applications . Patients ranked their answer on a 3-point Likert scale ranging from 1=not important to 3=very important to the question, “Which content topic is important for a psycho-oncological intervention?” Next, patients ranked their answer on a 3-point Likert scale ranging from 1=not suitable to 3=very suitable to the question, ”Which application is suitable for the mentioned content topics?”The 11-level visual analog scale of the Distress Thermometer is widely used to measure distress and has been validated in diverse oncology applications ,43. PatiThe Hornheider Screening Instrument (HSI) is a widely used German 7-item screening instrument to identify patients in need of psychosocial support . The shoThe EuroQoL 5-Dimension 3-Level Questionnaire (EQ-5D-3L) has been used in many clinical trials and methodological studies published in the peer-reviewed literature. It is a standardized instrument for describing and evaluating a patient’s general health status and can be used for clinical assessment of QoL . To measP<.05 was considered statistically significant.Descriptive statistics, mean and standard deviation, frequencies, percentages, and chi-square statistics for categorical variables were performed using SPSS 21 for Windows (IBM Corp). Statistical analysis was performed to search for a relationship between patient preferences for psycho-oncological eHealth care and psychological burden with distress, QoL, and need for psychosocial support. Data were normally distributed. Chi-square statistics were used to examine the data for associations between the psychological burden and the preference for psycho-oncological content topics and ePOAs. We computed for distress  and QoL  in a 3×2 distribution table and for HSI  in a 2×2 distribution table. For this purpose, the responses of items were dichotomized . Missing data only occurred for the patient preference surveys. The overall mean of missing values was estimated as 2.075%. Missing values were considered only if at least 80% of each of the questionnaires had been completed. Using the Little missing completely at random test, it was confirmed that the data were missing randomly. The expectation-maximization algorithm was used to input the missing data . All of Of the 1172 patients who responded, 716 (61.09%) datasets met the inclusion criteria, showed acceptable quality, and were included in the study. The mean age of participants was 50.2 (SD 10.3) years (range 25-83 years). Nearly 80.4% (576/716) of the patients were primarily diagnosed with cancer, and 12.2% (87/716) of participants were diagnosed with metastasis; 11.0% (79/716) were experiencing a recurrence of the past cancer diagnosis. The frequencies of other disease-related and demographic variables and mean values and standard deviations of the Distress Thermometer, EQ-5D-3L, and HSI questionnaires are presented in The 19 content topics for a psycho-oncological intervention were rated by the patients see . The higLower preference rates were reached by spirituality , sense-making , and sexuality .Almost all of the eHealth applications for conveying the content topics were considered by more than 50% as suitable. Web-based application/info home page  was considered to be the most suitable compared to other eHealth applications. Blogs or chats were considered suitable or very suitable . More than half considered the eHealth applications info email  and consultation hotline  suitable or very suitable. Videoconference was judged by the least number of patients  as suitable for psycho-oncological care see .Preferences for all content topics were equally distributed in the subgroups distress and QoL. Preferences were not dependent on high, middle, or low distress or high, middle, or low QoL. Also, in the context of needing psychosocial support, patients preferred the same content topics for a psycho-oncological intervention. We found no differences between participants with different levels of distress or QoL concerning the preferred content of eHealth interventions. Furthermore, time since diagnosis or prognosis as well as recruitment  had no influence on needs (data not shown).Our survey explored for the first time the perceived demands and needs for a psycho-oncological eHealth intervention among women with breast and gynecological cancer. Furthermore, we investigated whether there is a relationship between psychological burden  and content topic relevance. In this sample of 716 cancer-affected women, we found distinctively relevant content topics for eHealth interventions. The content topics of ability to cope, anxiety, depressive feelings, or adjustment to new life situations have a high impact on eHealth interventions and, in turn, reflect the needs and demands for psycho-oncological care of cancer-affected women. Spirituality, sense-making, and dealing with children had no high relevance for eHealth interventions in our sample. Furthermore, Web-based application/info home page, info email, and chats and blogs were identified as very suitable and suitable for conveying psycho-oncological content topics to the patients. We found that preferences for specific content topics and eHealth applications were equal between patients with high and low burden (experienced distress and QoL). In addition, the need for psychosocial support did not influence the demands and needs of the patients. To summarize, interestingly, women with cancer experience—independently of their psychological burden—have the same demands and needs for psycho-oncological content topics. Furthermore, they expressed the same demands for eHealth applications in psycho-oncological care.We found in our survey that the most preferred type of psycho-oncological eHealth interventions are Web-based applications or info emails. These results are in line with previous studies that also identified high preferences for eHealth applications ,33,34,49The psycho-oncological content topics that were evaluated for eHealth applications see  are simiOur survey study was based on a large sample (N=716) of patients diagnosed with breast cancer, gynecologic cancer, or both. Our use of various and novel recruitment strategies  led to a large proportion being included through the online questionnaire n=581). This shows that eHealth is especially targeting patients with eHealth literacy, and therefore our results can be considered as representative of these patients 1. This s. Breast Our findings show high preference rates for eHealth applications independently of experienced psychological burden among women with cancer. Furthermore, ePOAs may have a high benefit for women with cancer, especially when they address psycho-oncological content topics like anxiety, ability to cope, depressive feelings, self-esteem, or adjustment to new life situations. ePOAs have the potential to help patients overcome disease-related burden and reduce barriers in psychosocial care. However, they can encourage patients who they believe are not sufficiently burdened to participate in common psycho-oncological interventions ,59. Our