Recent advances in sialic acid-based active targeting chemoimmunotherapy promoting tumor shedding: a systematic review.

Tumors have always been a major public health concern worldwide, and attempts to look for effective treatments have never ceased. Sialic acid is known to be a crucial element for tumor development and its receptors are highly expressed on tumor-associated immune cells, which perform significant roles in establishing the immunosuppressive tumor microenvironment and further boosting tumorigenesis, progression, and metastasis. Obviously, it is essential to consider sophisticated crosstalk between tumors, the immune system, and preparations, and understand the links between pharmaceutics and immunology. Sialic acid-based chemoimmunotherapy enables active targeting drug delivery via mediating the recognition between the sialic acid-modified nano-drug delivery system represented by liposomes and sialic acid-binding receptors on tumor-associated immune cells, which inhibit their activity and utilize their homing ability to deliver drugs. Such a "Trojan horse" strategy has remarkably improved the shortcomings of traditional passive targeting treatments, unexpectedly promoted tumor shedding, and persistently induced robust immunological memory, thus highlighting its prospective application potential for targeting various tumors. Herein, we review recent advances in sialic acid-based active targeting chemoimmunotherapy to promote tumor shedding, summarize the current viewpoints on the tumor shedding mechanism, especially the formation of durable immunological memory, and analyze the challenges and opportunities of this attractive approach.

The Identification of RPL4 as a Hub Gene Associated with Goat Litter Size via Weighted Gene Co-Expression Network Analysis.

Reproduction in goats is a highly complex and dynamic process of life regulation, involving coordinated regulation from various aspects such as central nervous system regulation, reproductive system development, oocyte maturation, and fertilized egg development. In recent years, researchers have identified numerous genes associated with goat reproductive performance through high-throughput sequencing, single-cell sequencing, gene knockout, and other techniques. However, there is still an urgent need to explore marker genes related to goat reproductive performance. In this study, a single-cell RNA sequencing dataset of oocytes (GSE136005) was obtained from the Gene Expression Omnibus (GEO) database. Weighted Gene Co-expression Network Analysis (WGCNA) was utilized to identify modules highly correlated with goat litter size. Through gene function enrichment analysis, it was found that genes within the modules were mainly enriched in adhesive junctions, cell cycle, and other signaling pathways. Additionally, the top 30 hub genes with the highest connectivity in WGCNA were identified. Subsequently, using Protein-Protein Interaction (PPI) network analysis, the top 30 genes with the highest connectivity within the modules were identified. The intersection of hub genes, key genes in the PPI network, and differentially expressed genes (DEGs) led to the identification of the RPL4 gene as a key marker gene associated with reproductive capacity in goat oocytes. Overall, our study reveals that the RPL4 gene in oocytes holds promise as a biological marker for assessing goat litter size, deepening our understanding of the regulatory mechanisms underlying goat reproductive performance.

Durable protective efficiency provide by mRNA vaccines require robust immune memory to antigens and weak immune memory to lipid nanoparticles.

The Pegylated lipids in lipid nanoparticle (LNPs) vaccines have been found to cause acute hypersensitivity reactions in recipients, and generate anti-LNPs immunity after repeated administration, thereby reducing vaccine effectiveness. To overcome these challenges, we developed a new type of LNPs vaccine (SAPC-LNPs) which was co-modified with sialic acid (SA) - lipid derivative and cleavable PEG - lipid derivative. This kind of mRNA vaccine can target dendritic cells (DCs) and rapidly escape from early endosomes (EE) and lysosomes with a total endosomal escape rate up to 98 %. Additionally, the PEG component in SAPC-LNPs was designed to detach from the LNPs under the catalysis of carboxylesterase in vivo, which reduced the probability of PEG being attached to LNPs entering antigen-presenting cells. Compared with commercially formulated vaccines (1.5PD-LNPs), mice treated with SAPC-LNPs generated a more robust immune memory to tumor antigens and a weaker immune memory response to LNPs, and showed lower side effects and long-lasting protective efficiency. We also discovered that the anti-tumor immune memory formed by SAPC-LNPs mRNA vaccine was directly involved in the immune cycle to rattack tumor. This immune memory continued to strengthen with multiple cycles, supporting that the immune memory should be incorporated into the theory of tumor immune cycle.

Sialic acid-modified doxorubicin liposomes target tumor-related immune cells to relieve multiple inhibitions of CD8+ T cells.

In different types of cancer treatments, cancer-specific T cells are required for effective anticancer immunity, which has a central role in cancer immunotherapy. However, due to the multiple inhibitions of CD8+ T cells by tumor-related immune cells, CD8+ T-cell mediated antitumor immunotherapy has not achieved breakthrough progress in the treatment of solid tumors. Receptors for sialic acid (SA) are highly expressed in tumor-associated immune cells, so SA-modified nanoparticles are a drug delivery nanoplatform using tumor-associated immune cells as vehicles. To relieve the multiple inhibitions of CD8+ T cells by tumor-associated immune cells, we prepared SA-modified doxorubicin liposomes (SL-DOX, Scheme 1A). In our study, free SA decreased the toxicity of SL-DOX to tumor-associated immune cells. Compared with common liposomes, SL-DOX could inhibit tumor growth more effectively. It is worth noting that SL-DOX could not only kill tumor-related neutrophils and monocytes to relieve the multiple inhibitions of CD8+ T cells but also induce immunogenic death of tumor cells to promote the infiltration and differentiation of CD8+ T cells (Scheme 1B). Therefore, SL-DOX has potential value for the clinical therapeutic effect of CD8+ T cells mediating anti-tumor immunotherapy.

A Latent Hidden Markov Model for Process Data.

Response process data from computer-based problem-solving items describe respondents' problem-solving processes as sequences of actions. Such data provide a valuable source for understanding respondents' problem-solving behaviors. Recently, data-driven feature extraction methods have been developed to compress the information in unstructured process data into relatively low-dimensional features. Although the extracted features can be used as covariates in regression or other models to understand respondents' response behaviors, the results are often not easy to interpret since the relationship between the extracted features, and the original response process is often not explicitly defined. In this paper, we propose a statistical model for describing response processes and how they vary across respondents. The proposed model assumes a response process follows a hidden Markov model given the respondent's latent traits. The structure of hidden Markov models resembles problem-solving processes, with the hidden states interpreted as problem-solving subtasks or stages. Incorporating the latent traits in hidden Markov models enables us to characterize the heterogeneity of response processes across respondents in a parsimonious and interpretable way. We demonstrate the performance of the proposed model through simulation experiments and case studies of PISA process data.

Simultaneous dendritic cells targeting and effective endosomal escape enhance sialic acid-modified mRNA vaccine efficacy and reduce side effects.

mRNA vaccines are attractive prospects for the development of DC-targeted vaccines; however, no clinical success has been realized because, currently, it is difficult to simultaneously achieve DC targeting and efficient endosomal/lysosomal escape. Herein, we developed a sialic acid (SA)-modified mRNA vaccine that simultaneously achieved both. The SA modification promoted DCs uptake of lipid nanoparticles (LNPs) by 2 times, >90% of SA-modified LNPs rapidly escaped from early endosomes (EEs), avoided entering lysosomes, achieved mRNA simultaneously translated in ribosomes distributed in the cytoplasm and endoplasmic reticulum (ER), significantly improved the transfection efficiency of mRNA LNPs in DCs. Additionally, we applied cleavable PEG-lipids in mRNA vaccines for the first time and found this conducive to cellular uptake and DC targeting. In summary, SA-modified mRNA vaccines targeted DCs efficiently, and showed significantly higher EEs/lysosomal escape efficiency (90% vs 50%), superior tumor treatment effect, and lower side effects than commercially formulated mRNA vaccines.

Sialic acid-mediated photochemotherapy enhances infiltration of CD8+ T cells from tumor-draining lymph nodes into tumors of immunosenescent mice.

Immunoscenescence plays a key role in the initiation and development of tumors. Furthermore, immunoscenescence also impacts drug delivery and cancer therapeutic efficacy. To reduce the impact of immunosenescence on anti-tumor therapy, this experimental plan aimed to use neutrophils with tumor tropism properties to deliver sialic acid (SA)-modified liposomes into the tumor, kill tumor cells via SA-mediated photochemotherapy, enhance infiltration of neutrophils into the tumor, induce immunogenic death of tumor cells with chemotherapy, enhance infiltration of CD8+ T cells into the tumor-draining lymph nodes and tumors of immunosenescent mice, and achieve SA-mediated photochemotherapy. We found that CD8+ T cell and neutrophil levels in 16-month-old mice were significantly lower than those in 2- and 8-month-old mice; 16-month-old mice exhibited immunosenescence. The anti-tumor efficacy of SA-mediated non-photochemotherapy declined in 16-month-old mice, and tumors recurred after scabbing. SA-mediated photochemotherapy enhanced tumor infiltration by CD8+ T cells and neutrophils, induced crusting and regression of tumors in 8-month-old mice, inhibited metastasis and recurrence of tumors and eliminated the immunosenescence-induced decline in antitumor therapeutic efficacy in 16-month-old mice via the light-heat-chemical-immunity conversion.

Subtask analysis of process data through a predictive model.

Response process data collected from human-computer interactive items contain detailed information about respondents' behavioural patterns and cognitive processes. Such data are valuable sources for analysing respondents' problem-solving strategies. However, the irregular data format and the complex structure make standard statistical tools difficult to apply. This article develops a computationally efficient method for exploratory analysis of such process data. The new approach segments a lengthy individual process into a sequence of short subprocesses to achieve complexity reduction, easy clustering and meaningful interpretation. Each subprocess is considered a subtask. The segmentation is based on sequential action predictability using a parsimonious predictive model combined with the Shannon entropy. Simulation studies are conducted to assess the performance of the new method. We use a case study of PIAAC 2012 to demonstrate how exploratory analysis for process data can be carried out with the new approach.

Persistent immune response: Twice tumor exfoliation induced by sialic acid-modified vincristine sulfate liposomes.

Studies have shown that tumor-associated macrophages (TAMs) are crucial for the establishment and maintenance in immunosuppressive tumor immune microenvironment (TIME), which can help tumor cells to achieve immune escape and attenuate antitumor therapy. Siglecs, the receptors of sialic acid (SA), widely exist in TAMs, which could be targeted to disrupt TIME and inhibit tumor growth at the root. Therefore, a SA-modified VCR liposome was reported (VCR-SSAL). Cellular and pharmacodynamic experiments showed that VCR-SSAL exhibited strong TAMs targeting and tumor-killing ability. Interestingly, VCR-SSAL treatment induced a phenomenon in which the cancerous tissues were "fell off" from the growth site, after which the wound gradually healed. Three months after the wound healed, the mice whose tumors fell off were re-inoculated, and the tumor fell off again without treatment, with an exfoliation rate of 100%. We speculated that this special efficacy might be due to that VCR loaded in VCR-SSAL could activate adaptive immunity by inducing DNA damage, promoting cytotoxic T lymphocytes (CTLs) infiltration into tumor sites, and enhancing the antitumor immune response. Thus, this study might provide new insights into the application of traditional chemotherapeutic drugs.

What is the efficacy of dietary, nutraceutical, and probiotic interventions for the management of gastroesophageal reflux disease symptoms? A systematic literature review and meta-analysis.

BACKGROUND: Treatments for Gastroesophageal Reflux Disease (GERD) symptoms include pharmaceutical, surgical, dietary, and lifestyle behaviors; however, dietary interventions lack evidence synthesis. RESEARCH QUESTION: What is the effect of dietary, probiotic, and nutraceutical interventions on GERD symptoms, with or without pharmaceutical therapy, in adults with a history of GERD or functional dyspepsia compared to no intervention, placebo, or usual care? METHOD: A systematic review and meta-analysis was performed according to PRISMA. The search strategy was implemented in MEDLINE, CINAHL, CENTRAL, and Embase on the 28th October 2020 and updated to 27th July 2021. Intervention studies were eligible if they evaluated the effect of a dietary, nutraceutical, or probiotic intervention on GERD symptoms in adults with a history of GERD or functional dyspepsia. The internal validity of studies was assessed using the Academy Quality Criteria Checklist; Review Manager software was used to perform meta-analysis; and certainty in the body of evidence was assessed using GRADE. RESULTS: 6,608 study records were retrieved from the search, with 21 studies (n = 24 highly heterogenous intervention groups) included (n = 10 restrictive dietary interventions; n = 3 non-restrictive dietary interventions; n = 8 nutraceutical interventions; and n = 3 probiotic interventions). GERD symptoms were clinically and statistically improved by a test-based elimination diet (n = 1 study), low nickel diet (n = 1 study), probiotic yoghurt (n = 1 study), psyllium husk (n = 1 study), prickly pear and olive leaf extract supplement (n = 1 study), and melatonin, amino acid and b-group vitamin supplement (n = 1 study) according to qualitative synthesis. Ginger-containing supplements could be meta-analyzed, and improved incidence of GERD symptom alleviation (n = 2 studies, OR: 7.50 [95%CI: 3.62-15.54], GRADE: high). No clinically and/or statistically significant effects were found for the remaining n = 16 highly heterogenous interventions. CONCLUSION: Evidence to guide the dietary management of GERD symptoms is limited in scope, quality, and feasibility. Based on the limited evidence available, dietary GERD management should be long-term, individualized, and consider both dietary restrictions and/or additions. PROSPERO ID: CRD42021224082.

The Fate of Sialic Acid and PEG Modified Epirubicin Liposomes in Aged versus Young Cells and Tumor Mice Models.

In preclinical studies of young mice, nanoparticles showed excellent anti-tumor therapeutic effects by harnessing Peripheral Blood Monocytes (PBMs) and evading the immune system. However, the changes of age will inevitably affect PBMs and the immune system, and there is a serious lack of relevant research. Sialic acid (SA)-octadecylamine (ODA) was synthesized, and SA- or polyethylene glycol (PEG)-modified epirubicin (EPI) liposomes (EPI-SL and EPI-PL, respectively) were prepared to explore differences in antitumor treatment using 8-month-old and 8-week-old Kunming mice. Based on presented data, 8-month-old mice had more PBMs in peripheral blood than 8-week-old mice, and age differences resulted in different anti-tumor treatment effects following EPI-SL and EPI-PL treatment. Following EPI-PL administration, the tumor volume was significantly smaller in 8-week-old mice than in 8-month-old mice (* p < 0.05). Eight-month-old mice treated with EPI-SL (8M-SL) presented no damage to healthy tissue, with a 100% survival rate, and 50% mice in 8M-SL showed 'shedding' of tumor tissues from the growth site. Accordingly, 8-month-old mice treated with EPI-SL achieved the best therapeutic effect at different ages and with different liposomes. EPI-SL could improve the antitumor effect of 8-week-old and 8-month-old mice.

Branched PEG-modification: A new strategy for nanocarriers to evade of the accelerated blood clearance phenomenon and enhance anti-tumor efficacy.

PEGylation is one of the most successful technologies for reducing immunogenicity, improving the stability and circulation time of nanocarriers, and has been applied in the clinic for over three decades. However, linear PEG-modified nanocarriers have been found to induce anti-PEG IgM at the first injection, which triggers the accelerated blood clearance (ABC) phenomenon upon repeated injections. Furthermore, clinical and research evidence has revealed that anti-PEG antibodies also cause serious complement activation-related pseudoallergies (CARPA), which greatly reduce the safety of linear PEGylated nanocarriers. In this study, as an alternative to linear PEG, branched PEG was selected owing to its low antigenicity. We pioneer the use of branched PEG lipid derivatives [DSPE-mPEG2,n (n = 2, 10, and 20 kDa)] to modify nanoemulsions (PE2,n) and liposomes (PL2,n). Upon characterization, PE2,n and PL2,n showed similar physicochemical properties to linear DSPE-mPEG2000-modified nanocarriers in terms of size, polydispersity index (PDI), and zeta potential. However, our pharmacokinetics study surprisingly indicated that PE2,n and PL2,n did not induce the ABC phenomenon after repeated injection. This may be attributed to the fact that PE2,n and PL2,n induced noticeably lower levels of anti-PEG IgM than linear PEG-modified nanocarriers and did not activate the complement system. Furthermore, we are the first to investigate the anti-tumor efficacy of DSPE-mPEG2,n-modified liposomal doxorubicin (DOX). The pharmacodynamic experiments showed that DSPE-mPEG2,n-m-modified liposomal DOX had better in vivo anti-tumor effects than linear DSPE-mPEG2000-modified liposomes. Therefore, we speculate that DSPE-mPEG2,n-modified nanocarriers possess promising prospects in avoiding the ABC phenomenon, reducing CARPA, and improving the anti-tumor efficacy of encapsulated drugs.

Discovery in polyethylene glycol immunogenicity: The characteristic of intergenerational inheritance of anti-polyethylene glycol IgG.

Several studies have reported the prevalence of anti-polyethylene glycol (PEG) antibodies (APAs) in healthy people, highlighting the widespread existence of APAs. The prevalence of anti-PEG immunoglobulin (Ig)G is significantly negatively correlated with age. Here, we used Wistar rats as model organism to examine whether APAs in parental rats can affect the production of antibodies in their offspring. After being pre-stimulated with blank PEGylated nanoemulsions (PE) to induce APAs production, parental rats were paired in cages. The presence of antibodies in the parents and offspring was detected using enzyme-linked immunosorbent assay. The presence of antibodies in the parental rats led to significant anti-PEG IgG positivity in their offspring, indicating that anti-PEG IgG exhibits intergenerational inheritance. Moreover, anti-PEG IgG in the offspring rats could bind to PE and accelerate its blood clearance. To the best of our knowledge, this is the first report on the intergenerational properties of APAs.

Evasion of the accelerated blood clearance phenomenon by branched PEG lipid derivative coating of nanoemulsions.

PEGylation increases the circulation time of the nanocarrier, but also triggers accelerated blood clearance (ABC) phenomenon. It is well-known that the ABC phenomenon results in shortened blood circulation and aberrant increase in liver and spleen accumulation, which greatly limits the application of PEGylated nano-preparations. For many years, researchers have been working hard to find ways to reduce or eliminate the ABC phenomenon. Previous studies have focused on PEG molecular weight and PEG alternative materials, but there has never been any research on the effect of different PEG chain types on the ABC phenomenon. Therefore, 40 kDa molecular weight of linear PEG lipid derivatives (DSPE-mPEG40k) and branched PEG lipid derivatives (DSPE-mPEG2,40k) were selected to modify nanoemulsions to explore the influence of distinct PEG chain types on avoiding the ABC phenomenon for the first time. We pioneer the use of linear and branched PEG lipid derivatives (DSPE-mPEG40k and DSPE-mPEG2,40k) to modify nanoemulsions (PE40k and PE2,40k). Upon characterization, PE40k and PE2,40k showed good physicochemical properties in the aspect of size, polydispersity index (PDI value), and zeta potential. Surprisingly, the pharmacokinetics study indicated that repeated injection of PE40k and PE2,40k did not trigger the ABC phenomenon. More importantly, PE2,40k possessed a long circulation time and did not cause ABC phenomenon after repeated injection. This may be attributed to the fact that PE2,40k induced noticeably lower anti-PEG IgM levels compared to linear PEG-modified nanocarriers and did not activate the complement system. Therefore, we speculate that DSPE-mPEG2,40k-modified nanocarriers possess promising prospects in avoiding the ABC phenomenon, which may improve the possibility of wide application of nanoformulations.

A preliminary study of the innate immune memory of Kupffer cells induced by PEGylated nanoemulsions.

The accelerated blood clearance (ABC) phenomenon describes a dilemma of polyethylene glycol (PEG) applied in drug delivery system (DDS) caused by its immunogenicity, that results in the enhanced blood clearance rate and increased hepatic and splenic accumulation after secondary injection of PEGylated nanocarriers. However, the ABC index, as the judgement of ABC phenomenon, only describes the accelerated blood clearance rate, but ignores the enhanced hepatic and splenic accumulation. Therefore, we proposed the hepatic accumulation (HA) index and the splenic accumulation (SA) index as supplements for assessing the ABC phenomenon, to emphasize the contribution of liver and spleen, especially the liver, possessing the most population of tissue resident macrophages. By altering the first injection site from the tail vein to the liver portal vein, there was no impact on anti-PEG IgM production, and the secondary hepatic accumulation of PEGylated nanoemulsions (PE) was observed to be proportionate to the first PE stimulation strength on the liver. We also determined that Kupffer cells (KCs) were the main contributor to this enhancement. On this basis, we revealed a definite phenomenon that PE could induce innate immune memory in KCs, by enhancing the phagocytosis of KCs toward PE during the secondary stimulation. The PE-stimulated KCs could carry this memory to the naïve rats through adoptive transfer, resulting in increased hepatic accumulation in the recipient rats without antibody production. Studies examining the phagocytosis of KCs in vivo, ex vivo and in vitro revealed that the memory of KCs against PE triggered by first-stimulated PE could be maintained independently of other cells or components until 21 days after the first stimulation, and possessing specificity to PEG, which was invalid to long-circulating GE (GM1 modified nanoemulsions). The discovery of immune memory in KCs induced by PE highlights the importance of focusing on the relationship between the innate immune system and PEGylated nanocarriers during the development of DDS to improve medication safety in the clinic.

ProcData: An R Package for Process Data Analysis.

Process data refer to data recorded in log files of computer-based items. These data, represented as timestamped action sequences, keep track of respondents' response problem-solving behaviors. Process data analysis aims at enhancing educational assessment accuracy and serving other assessment purposes by utilizing the rich information contained in response processes. The R package ProcData presented in this article is designed to provide tools for inspecting, processing, and analyzing process data. We define an S3 class 'proc' for organizing process data and extend generic methods summary and print for 'proc'. Feature extraction methods for process data are implemented in the package for compressing information in the irregular response processes into regular numeric vectors. ProcData also provides functions for making predictions from neural-network-based sequence models. In addition, a real dataset of response processes from the climate control item in the 2012 Programme for International Student Assessment is included in the package.

Sequential administration of sialic acid-modified liposomes as carriers for epirubicin and zoledronate elicit stronger antitumor effects with reduced toxicity.

Combined administration of drugs can improve efficacy and reduce toxicity; therefore, this combination approach has become a routine method in cancer therapy. The main combination regimens are sequential, mixed (also termed "cocktail"), and co-loaded; however, other combinations, such as administration of synergistic drugs and the use of formulations with different mechanisms of action, may exert better therapeutic effects. Tumor-associated macrophages (TAMs) play functional roles throughout tumor progression and exhibit characteristic phenotypic plasticity. Sialic acid (SA)-modified epirubicin liposomes (S-E-L) and SA-modified zoledronate liposomes (S-Z-L) administered separately kill TAMs, reverse their phenotype, and achieve antitumor effects. In this study, we examined the effects of a two-treatment combination for drug delivery, using sequential, mixed, and co-loaded drug delivery. We found that therapeutic effects differed between administration methods: mixed administration of S-E-L and S-Z-L, co-loaded administration of SA-modified liposomes (S-ZE-C), and sequential administration of S-E-L injected 24 h after S-Z-L did not inhibit tumor growth; however, sequential administration of S-Z-L injected 24 h after S-E-L resulted in no tumor growth, no toxicity to noncancerous tissue, and no death of mice, and exhibited 25% tumor shedding. Thus, our results thus encourage the further development of combined therapies for nanomedicines based on the mechanisms investigated here.

Influence of Dose on Neutrophil-Mediated Delivery of Nanoparticles for Tumor-Targeting Therapy Strategies.

It is well known that neutrophil-mediated delivery of therapeutic agents is a promising method for treating tumors. However, owing to the limited number and limited uptake ability of neutrophils, determining a reasonable dose has become an urgent problem to be solved. Furthermore, the number of nanoparticles is far greater than the number of neutrophils at normal doses, which causes excessive nanoparticles to reach nontargeted organs or tissues, leading to serious adverse effects. To address these problems, a neutrophil-targeting delivery system (DiR-DADGC-L) based on DiR-labeled and butanedioic acid (DA)-linked 5-amino-3,5-dideoxy-D-Glycerol-D-galactonanulose-cholesterol conjugate (DADGC) was designed to improve the efficiency of hitchhiking neutrophils through the specific binding of sialic acid (SA) to L-selectin (SA-binding receptor, expressed on neutrophils). DiR-DADGC-L was prepared with favorable particle size and encapsulation efficiency (%EE) to deliver DiR into neutrophils. Subsequently, diverse doses of DiR-DADGC-L were injected intravenously into S180 tumor-bearing and cyclophosphamide-depleted (CTX-D) S180 tumor-bearing mice to evaluate the in vivo behavior of liposomes. The results verified the following: a) The content of DiR-DADGC-L in neutrophils accounts for approximately 14.5% of the content of DiR-DADGC-L in plasma, and the uptake capacity of neutrophils remains unchanged under different doses, and b) both neutrophils and the enhanced permeability and retention (EPR) effect might exert significant roles in tumor treatment. As for the neutrophil-mediated delivery system, higher doses are not necessarily appropriate, and a lower dose may achieve an unexpected effect. It will be wise to determine an optimum dose to improve delivery efficiency.

An exploratory analysis of the latent structure of process data via action sequence autoencoders.

Computer simulations have become a popular tool for assessing complex skills such as problem-solving. Log files of computer-based items record the human-computer interactive processes for each respondent in full. The response processes are very diverse, noisy, and of non-standard formats. Few generic methods have been developed to exploit the information contained in process data. In this paper we propose a method to extract latent variables from process data. The method utilizes a sequence-to-sequence autoencoder to compress response processes into standard numerical vectors. It does not require prior knowledge of the specific items and human-computer interaction patterns. The proposed method is applied to both simulated and real process data to demonstrate that the resulting latent variables extract useful information from the response processes.

Workplace programmes for supporting breast-feeding: a systematic review and meta-analysis.

OBJECTIVE: To critically review the literature regarding workplace breast-feeding interventions and to assess their impact on breast-feeding indicators. DESIGN: A systematic review and meta-analysis was conducted. Electronic searches for workplace intervention studies to support breast-feeding, without restriction on language or study design, were performed in PubMed, CENTRAL, CINAHL, Embase, Web of Science, Business Source Complete, ProQuest-Sociology and ProQuest-Social Science to 13 April 2020. A meta-analysis of the pooled effect of the programmes on breast-feeding indicators was conducted. RESULTS: The search identified 10 215 articles; fourteen studies across eighteen publications met eligibility criteria. Programmes were delivered in the USA (n 10), Turkey (n 2), Thailand (n 1) or Taiwan (n 1). There were no randomised controlled trials. The pooled OR for exclusive breast-feeding at 3 or 6 months for participants v. non-participants of three non-randomised controlled studies was 3·21 (95 % CI 1·70, 6·06, I2 = 22 %). Despite high heterogeneity, other pooled outcomes were consistently in a positive direction with acceptable CI. Pooled mean duration of breast-feeding for five single-arm studies was 9·16 months (95 % CI 8·25, 10·07). Pooled proportion of breast-feeding at 6 months for six single-arm studies was 0·76 (95 % CI 0·66, 0·84) and breast-feeding at 12 months for three single-arm studies was 0·41 (95 % CI 0·22, 0·62). Most programmes were targeted at mothers; two were targeted at expectant fathers. CONCLUSIONS: Workplace programmes may be effective in promoting breast-feeding among employed mothers and partners of employed fathers. However, no randomised controlled trials were identified, and better-quality research on workplace interventions to improve breast-feeding is needed.