Structure-based validation can drastically underestimate error rate in proteome-wide cross-linking mass spectrometry studies.

Thorough quality assessment of novel interactions identified by proteome-wide cross-linking mass spectrometry (XL-MS) studies is critical. Almost all current XL-MS studies have validated cross-links against known three-dimensional structures of representative protein complexes. Here, we provide theoretical and experimental evidence demonstrating that this approach can drastically underestimate error rates for proteome-wide XL-MS datasets, and propose a comprehensive set of four data-quality metrics to address this issue.

Handcuffing intrinsically disordered regions in Mlh1-Pms1 disrupts mismatch repair.

The DNA mismatch repair (MMR) factor Mlh1-Pms1 contains long intrinsically disordered regions (IDRs) whose exact functions remain elusive. We performed cross-linking mass spectrometry to identify interactions within Mlh1-Pms1 and used this information to insert FRB and FKBP dimerization domains into their IDRs. Baker's yeast strains bearing these constructs were grown with rapamycin to induce dimerization. A strain containing FRB and FKBP domains in the Mlh1 IDR displayed a complete defect in MMR when grown with rapamycin. but removing rapamycin restored MMR functions. Strains in which FRB was inserted into the IDR of one MLH subunit and FKBP into the other subunit were also MMR defective. The MLH complex containing FRB and FKBP domains in the Mlh1 IDR displayed a rapamycin-dependent defect in Mlh1-Pms1 endonuclease activity. In contrast, linking the Mlh1 and Pms1 IDRs through FRB-FKBP dimerization inappropriately activated Mlh1-Pms1 endonuclease activity. We conclude that dynamic and coordinated rearrangements of the MLH IDRs both positively and negatively regulate how the MLH complex acts in MMR. The application of the FRB-FKBP dimerization system to interrogate in vivo functions of a critical repair complex will be useful for probing IDRs in diverse enzymes and to probe transient loss of MMR on demand.

α-2,6-sialic acid/IgG anti-dsDNA ratios correlate with human lupus disease activity and possible mechanisms: A pilot study.

OBJECTIVE: To study the association of α2,6-sialic acid (SIA) content in serum IgG anti-dsDNA with human systemic lupus erythematosus disease activity index (SLEDAI) and the effect of sialylated and desialylated (deSIA) IgG anti-dsDNA on lupus B cells. METHODS: Blood from lupus patients was collected to determine the ratio of SIA in isolated IgG anti-dsDNA over serum IgG anti-dsDNA (SIA/IgG anti-dsDNA) ratios, which were plotted against SLEDAI using a receiver-operating-characteristics curve. Lupus B cells were cultured in vitro with chimeric sialylated IgG anti-dsDNA and its deSIA form. Culture supernatants were assayed for anti-inflammatory IL-10 and SIA/IgG anti-dsDNA ratios, which were compared among different pre-treatment groups using t-tests. RESULTS: The area-under-the-curve (AUC) for anti-dsDNA levels against SLEDAI was 0.791 positively (95% confidence interval [C.I.]: 0.699-0.884) and SIA/IgG anti-dsDNA ratios against SLEDAI yielded an AUC of 0.705 inversely (95% C.I: 0.601-0.809): not significantly different. SIA/IgG anti-dsDNA ratios discriminated significantly between patients without and patients with proteinuria (p = .046). SIA/IgG anti-dsDNA ratios correlated significantly and positively with serum C3c and C4 levels. Pre-treatment with IgG anti-dsDNA and its immune complexes (dsDNA/IgG anti-dsDNA IC) induced higher IL-10 from lupus B cells than medium pre-treatment (most p < .01 from day 2 to day 5 culture). DeSIA IgG anti-dsDNA IC induced lower IL-10 (p < .05) and lower SIA/IgG anti-dsDNA ratios (p < .001) from lupus B cells than medium and dsDNA pre-treatment. CONCLUSION: α2,6-SIA/IgG anti-dsDNA ratios inversely forecasted SLEDAI scores. Possible mechanisms may be due to the different effects of sialylated and deSIA IgG anti-dsDNA on lupus B cells in terms of IL-10 secretion and SIA/IgG anti-dsDNA ratios.

MaXLinker: Proteome-wide Cross-link Identifications with High Specificity and Sensitivity.

Protein-protein interactions play a vital role in nearly all cellular functions. Hence, understanding their interaction patterns and three-dimensional structural conformations can provide crucial insights about various biological processes and underlying molecular mechanisms for many disease phenotypes. Cross-linking mass spectrometry (XL-MS) has the unique capability to detect protein-protein interactions at a large scale along with spatial constraints between interaction partners. The inception of MS-cleavable cross-linkers enabled the MS2-MS3 XL-MS acquisition strategy that provides cross-link information from both MS2 and MS3 level. However, the current cross-link search algorithm available for MS2-MS3 strategy follows a "MS2-centric" approach and suffers from a high rate of mis-identified cross-links. We demonstrate the problem using two new quality assessment metrics ["fraction of mis-identifications" (FMI) and "fraction of interprotein cross-links from known interactions" (FKI)]. We then address this problem, by designing a novel "MS3-centric" approach for cross-link identification and implementing it as a search engine named MaXLinker. MaXLinker outperforms the currently popular search engine with a lower mis-identification rate, and higher sensitivity and specificity. Moreover, we performed human proteome-wide cross-linking mass spectrometry using K562 cells. Employing MaXLinker, we identified a comprehensive set of 9319 unique cross-links at 1% false discovery rate, comprising 8051 intraprotein and 1268 interprotein cross-links. Finally, we experimentally validated the quality of a large number of novel interactions identified in our study, providing a conclusive evidence for MaXLinker's robust performance.

[Improving the Rate of Eating Safety Guidance Implementation Among the Elderly].

BACKGROUND & PROBLEM: The provision by nurses of effective swallowing assessments and eating safety guidance improves eating safety in the elderly. The authors of this study found that elderly clients experienced a high proportion of aspiration pneumonia after choking episodes and that the rate of implementation of eating safety guidance among these clients by nursing staff was only 64.6%. The problems identified included a lack of education and training related to eating safety for the elderly, inconsistent health education methods, oral health education only, lack of unified health education content, and lack of proper health education guidance aids. PURPOSE: To raise the rate of implementing eating safety guidance among the elderly from 64.6% to 90.0%. RESOLUTION: The project included promoting an eating safety guidance workflow for the elderly using cross-team collaboration, using human body models and food models, promoting oral healthcare and oral exercises, using multilingual instructional leaflets and videos on eating safety and hygiene education, promoting a treasure hunting activity to the elderly related to eating safely using a food texture selection chart, and implementing a workshop on simulated eating safety scenarios. RESULTS: After project implementation, the eating safety guidance implementation rate increased from 64.6% to 92.1%, demonstrating that the intervention measures achieved remarkable results. CONCLUSIONS: Formulating care procedures and cooperating across teams to draft concrete and feasible improvement measures effectively increased the rate of eating safety guidance implementation for elderly clients by nursing staff.

Efficient cell delivery mediated by lipid-specific endosomal escape of supercharged branched peptides.

Various densely charged polycationic species, whether of biological or synthetic origin, can penetrate human cells, albeit with variable efficiencies. The molecular underpinnings involved in such transport remain unclear. Herein, we assemble 1, 2 or 3 copies of the HIV peptide TAT on a synthetic scaffold to generate branched cell-permeable prototypes with increasing charge density. We establish that increasing TAT copies dramatically increases the cell penetration efficiency of the peptides while simultaneously enabling the efficient cytosolic delivery of macromolecular cargos. Cellular entry involves the leaky fusion of late endosomal membranes enriched with the anionic lipid BMP. Derivatives with multiple TAT branches induce the leakage of BMP-containing lipid bilayers, liposomal flocculation, fusion and an increase in lamellarity. In contrast, while the monomeric counterpart 1TAT binds to the same extent and causes liposomal flocculation, 1TAT does not cause leakage, induce fusion or a significant increase in lamellarity. Overall, these results indicate that an increase in charge density of these branched structures leads to the emergence of lipid specific membrane-disrupting and cell-penetrating activities.

Targeting Nanotechnologies for the Treatment of Thrombosis and Cardiovascular Disease.

Thrombosis is characterized by the formation of in vivo blood clots that are localized within arterial or venous blood vessels. These thrombi form beyond the need for physiologically healthy hemostatic responses and can lead to significant medical issues for affected individuals. Unfortunately, the existing standard-of-care therapies for treating thrombosis are systemic in their therapeutic design; therefore, they interfere with the patient's physiological hemostasis. Examples of the severe clinical side effects commonly associated with currently available therapies include, but are not limited to, bleeding complications. Therefore, there is a profound demand for novel therapeutic interventions that can circumvent these debilitating complications, while offering improved therapeutic efficacy. Recent advancements in nanotechnology present an opportunity to develop novel and improved drug delivery systems to meet this clinical demand. Preclinical investigations have begun to uncover the potential of nanotechnology, particularly in the treatment of thrombosis and also in nonhemostatic cardiovascular diseases. This article reviews recent preclinical studies aimed at developing a diverse array of different nanotechnologies for treating thrombosis as well as heart diseases. This review will also outline the limitations with current nanotechnologies and what challenges need to be overcome to translate these novel therapies to the clinic.

Eradication Efficacy of Modified Dual Therapy Compared with Bismuth-Containing Quadruple Therapy as a First-Line Treatment of Helicobacter pylori.

OBJECTIVES: This study assessed the effectiveness, adverse events, patient adherence, and costs of modified dual therapy compared with bismuth-containing quadruple therapy for treating Helicobacter pylori infection in Chinese patients. We also sought to determine whether modified dual therapy could be used as an alternative first-line treatment for H. pylori infection. METHODS: A total of 232 H. pylori-infected, treatment-naive patients were enrolled in this open-label, randomized controlled clinical trial. Patients were randomly allocated into 2 groups: the 14-day modified dual therapy group and the bismuth-containing quadruple therapy group. Eradication rates, drug-related adverse events, patient compliance, and drug costs were compared between the 2 groups. RESULTS: The modified dual therapy group achieved eradication rates of 87.9%, 91.1%, and 91.1% as determined by the intention-to-treat, per-protocol, and modified intention-to-treat analyses, respectively. The eradication rates were similar compared with the bismuth-containing quadruple therapy group: 89.7%, 91.2%, and 90.4%. In addition, modified dual therapy ameliorated variations in the CYP2C19, IL-1B-511, and H. pylori VacA genotypes. There were no significant differences in the compliance rates between the 2 groups. The modified dual therapy group exhibited significantly less overall side effects compared with the bismuth-containing quadruple therapy group (P < 0.001). Furthermore, the cost of medications in the modified dual therapy was lower compared with that in the bismuth-containing quadruple therapy. CONCLUSIONS: Modified dual therapy at high dose and administration frequency is equally effective and safer and less costly compared with bismuth-containing quadruple therapy.

Ligand-Functionalized Poly(ethylene glycol) Particles for Tumor Targeting and Intracellular Uptake.

Drug carriers typically require both stealth and targeting properties to minimize nonspecific interactions with healthy cells and increase specific interaction with diseased cells. Herein, the assembly of targeted poly(ethylene glycol) (PEG) particles functionalized with cyclic peptides containing Arg-Gly-Asp (RGD) (ligand) using a mesoporous silica templating method is reported. The influence of PEG molecular weight, ligand-to-PEG molecule ratio, and particle size on cancer cell targeting to balance stealth and targeting of the engineered PEG particles is investigated. RGD-functionalized PEG particles (PEG-RGD particles) efficiently target U-87 MG cancer cells under static and flow conditions in vitro, whereas PEG and cyclic peptides containing Arg-Asp-Gly (RDG)-functionalized PEG (PEG-RDG) particles display negligible interaction with the same cells. Increasing the ligand-to-PEG molecule ratio improves cell targeting. In addition, the targeted PEG-RGD particles improve cell uptake via receptor-mediated endocytosis, which is desirable for intracellular drug delivery. The PEG-RGD particles show improved tumor targeting (14% ID g-1) when compared with the PEG (3% ID g-1) and PEG-RDG (7% ID g-1) particles in vivo, although the PEG-RGD particles show comparatively higher spleen and liver accumulation. The targeted PEG particles represent a platform for developing particles aimed at balancing nonspecific and specific interactions in biological systems.

An l- to d-Amino Acid Conversion in an Endosomolytic Analog of the Cell-penetrating Peptide TAT Influences Proteolytic Stability, Endocytic Uptake, and Endosomal Escape.

Cell-penetrating peptides (CPPs) are well established as delivery agents for otherwise cell-impermeable cargos. CPPs can also theoretically be used to modulate intracellular processes. However, their susceptibility to proteolytic degradation often limits their utility in these applications. Previous studies have explored the consequences for cellular uptake of converting the residues in CPPs from l- to d-stereochemistry, but conflicting results have been reported and specific steps en route to intracellular activity have not been explored. Here we use dimeric fluorescence TAT as a model CPP to explore the broader consequences of l- to d-stereochemical conversion. We show that inversion of chirality provides protease resistance without altering the overall mode of cellular entry, a process involving endocytic uptake followed by endosomal escape and cytosolic access. However, whereas inversion of chirality reduces endocytic uptake, the d-peptide, once in the endosome, is significantly more prone to escape than its l-counterpart. Moreover, the d-peptide is retained in the cytosol of cells for several days, whereas the l-peptide is degraded within hours. Notably, while the l-peptide is relatively innocuous to cells, the d-peptide exerts a prolonged anti-proliferative activity. Together, our results establish connections between chirality, protease resistance, cellular penetration, and intracellular activity that may be useful for the development of future delivery agents with improved properties.

Self-Assembled Metal-Phenolic Networks on Emulsions as Low-Fouling and pH-Responsive Particles.

Interfacial self-assembly is a powerful organizational force for fabricating functional nanomaterials, including nanocarriers, for imaging and drug delivery. Herein, the interfacial self-assembly of pH-responsive metal-phenolic networks (MPNs) on the liquid-liquid interface of oil-in-water emulsions is reported. Oleic acid emulsions of 100-250 nm in diameter are generated by ultrasonication, to which poly(ethylene glycol) (PEG)-based polyphenolic ligands are assembled with simultaneous crosslinking by metal ions, thus forming an interfacial MPN. PEG provides a protective barrier on the emulsion phase and renders the emulsion low fouling. The MPN-coated emulsions have a similar size and dispersity, but an enhanced stability when compared with the uncoated emulsions, and exhibit a low cell association in vitro, a blood circulation half-life of ≈50 min in vivo, and are nontoxic to healthy mice. Furthermore, a model anticancer drug, doxorubicin, can be encapsulated within the emulsion phase at a high loading capacity (≈5 fg of doxorubicin per emulsion particle). The MPN coating imparts pH-responsiveness to the drug-loaded emulsions, leading to drug release at cell internalization pH and a potent cell cytotoxicity. The results highlight a straightforward strategy for the interfacial nanofabrication of pH-responsive emulsion-MPN systems with potential use in biomedical applications.

Membrane Oxidation Enables the Cytosolic Entry of Polyarginine Cell-penetrating Peptides.

Arginine-rich peptides can penetrate cells and consequently be used as delivery agents in various cellular applications. The activity of these reagents is often context-dependent, and the parameters that impact cell entry are not fully understood, giving rise to variability and limiting progress toward their usage. Herein, we report that the cytosolic penetration of linear polyarginine peptides is dependent on the oxidation state of the cell. In particular, we find that hypoxia and cellular antioxidants inhibit cell penetration. In contrast, oxidants promote cytosolic cell entry with an efficiency proportional to the level of reactive oxygen species generated within membranes. Moreover, an antibody that binds to oxidized lipids inhibits cell penetration, whereas extracellularly administered pure oxidized lipids enhance peptide transport into cells. Overall, these data indicate that oxidized lipids are capable of mediating the transport of polyarginine peptides across membranes. These data may also explain variability in cell-penetrating peptide performance in different experimental conditions. These new findings therefore provide new opportunities for the rational design of future cell-permeable compounds and for the optimization of delivery protocols.

Protein delivery into live cells by incubation with an endosomolytic agent.

We report that a tetramethylrhodamine-labeled dimer of the cell-penetrating peptide TAT, dfTAT, penetrates live cells by escaping from endosomes with high efficiency. By mediating endosomal leakage, dfTAT also delivers proteins into cultured cells after a simple co-incubation procedure. We achieved cytosolic delivery in several cell lines and primary cells and observed that only a relatively small amount of material remained trapped inside endosomes. Delivery did not require a binding interaction between dfTAT and a protein, multiple molecules could be delivered simultaneously, and delivery could be repeated. dfTAT-mediated delivery did not noticeably affect cell viability, cell proliferation or gene expression. dfTAT-based intracellular delivery should be useful for cell-based assays, cellular imaging applications and the ex vivo manipulation of cells.

Characterization of the stability and bio-functionality of tethered proteins on bioengineered scaffolds: implications for stem cell biology and tissue repair.

Various engineering applications have been utilized to deliver molecules and compounds in both innate and biological settings. In the context of biological applications, the timely delivery of molecules can be critical for cellular and organ function. As such, previous studies have demonstrated the superiority of long-term protein delivery, by way of protein tethering onto bioengineered scaffolds, compared with conventional delivery of soluble protein in vitro and in vivo. Despite such benefits little knowledge exists regarding the stability, release kinetics, longevity, activation of intracellular pathway, and functionality of these proteins over time. By way of example, here we examined the stability, degradation and functionality of a protein, glial-derived neurotrophic factor (GDNF), which is known to influence neuronal survival, differentiation, and neurite morphogenesis. Enzyme-linked immunosorbent assays (ELISA) revealed that GDNF, covalently tethered onto polycaprolactone (PCL) electrospun nanofibrous scaffolds, remained present on the scaffold surface for 120 days, with no evidence of protein leaching or degradation. The tethered GDNF protein remained functional and capable of activating downstream signaling cascades, as revealed by its capacity to phosphorylate intracellular Erk in a neural cell line. Furthermore, immobilization of GDNF protein promoted cell survival and differentiation in culture at both 3 and 7 days, further validating prolonged functionality of the protein, well beyond the minutes to hours timeframe observed for soluble proteins under the same culture conditions. This study provides important evidence of the stability and functionality kinetics of tethered molecules.

Synthesis and pharmacological characterization of 2-aminobenzaldehyde oxime analogs as dual inhibitors of neutrophil elastase and proteinase 3.

Proteinase 3 (Pr3), and human neutrophil elastase (HNE) are two major neutrophilic serine proteases (NsPs) expressed in neutrophil azurophil granules. Emerging data suggest that excessive release of proteases mediates tissue damage, and therefore prolonged neutrophil accumulation has an important role in the pathogenesis of many diseases. Thus, HNE and Pr3 inhibitors may prove to be targets for the generation of agents in the treatment of neutrophilic inflammatory disease. Sivelestat is the only commercially available selective HNE inhibitor. Therefore, sivelestat was chosen as the model structure in an attempt to obtain more potent anti-NsPs agents. In the present study, a series 2-aminobenzaldehyde oxime and 2-aminobenzoate analogs were synthesized and their inhibitory effects on NsPs (CatG, Pr3, and HNE) were determined, respectively. The results of structure-activity relationships studies concluded that a hydroxyl oxime moiety plays an important role in ligand-enzyme affinity through hydrogen bonding. As compound 6 had more potency and showed dual inhibitory effects on NE and Pr3, both in vitro and in vivo experiments were carried out to evaluate its selectivity, effects in cell-based assays, and efficacy in models of inflammation and damage. Compound 6 had the potential to reduce paw edema induced by LPS and HNE, as well as acute lung injury, and may be approved as a candidate for the development of new agents in the treatment of neutrophilic inflammatory diseases.

Intraoperative AI-assisted early prediction of parathyroid and ischemia alert in endoscopic thyroid surgery.

BACKGROUND: The preservation of parathyroid glands is crucial in endoscopic thyroid surgery to prevent hypocalcemia and related complications. However, current methods for identifying and protecting these glands have limitations. We propose a novel technique that has the potential to improve the safety and efficacy of endoscopic thyroid surgery. PURPOSE: Our study aims to develop a deep learning model called PTAIR 2.0 (Parathyroid gland Artificial Intelligence Recognition) to enhance parathyroid gland recognition during endoscopic thyroidectomy. We compare its performance against traditional surgeon-based identification methods. MATERIALS AND METHODS: Parathyroid tissues were annotated in 32 428 images extracted from 838 endoscopic thyroidectomy videos, forming the internal training cohort. An external validation cohort comprised 54 full-length videos. Six candidate algorithms were evaluated to select the optimal one. We assessed the model's performance in terms of initial recognition time, identification duration, and recognition rate and compared it with the performance of surgeons. RESULTS: Utilizing the YOLOX algorithm, we developed PTAIR 2.0, which demonstrated superior performance with an AP50 score of 92.1%. The YOLOX algorithm achieved a frame rate of 25.14 Hz, meeting real-time requirements. In the internal training cohort, PTAIR 2.0 achieved AP50 values of 94.1%, 98.9%, and 92.1% for parathyroid gland early prediction, identification, and ischemia alert, respectively. Additionally, in the external validation cohort, PTAIR outperformed both junior and senior surgeons in identifying and tracking parathyroid glands (p < 0.001). CONCLUSION: The AI-driven PTAIR 2.0 model significantly outperforms both senior and junior surgeons in parathyroid gland identification and ischemia alert during endoscopic thyroid surgery, offering potential for enhanced surgical precision and patient outcomes.

Accurate preoperative prediction of nodal metastasis in papillary thyroid microcarcinoma: Towards optimal management of patients.

OBJECTIVE: To enhance the accuracy in predicting lymph node metastasis (LNM) preoperatively in patients with papillary thyroid microcarcinoma (PTMC), refining the "low-risk" classification for tailored treatment strategies. METHODS: This study involves the development and validation of a predictive model using a cohort of 1004 patients with PTMC undergoing thyroidectomy along with central neck dissection. The data was divided into a training cohort (n = 702) and a validation cohort (n = 302). Multivariate logistic regression identified independent LNM predictors in PTMC, leading to the construction of a predictive nomogram model. The model's performance was assessed through ROC analysis, calibration curve analysis, and decision curve analysis. RESULTS: Identified LNM predictors in PTMC included age, tumor maximum diameter, nodule-capsule distance, capsular contact length, bilateral suspicious lesions, absence of the lymphatic hilum, microcalcification, and sex. Especially, tumors larger than 7 mm, nodules closer to the capsule (less than 3 mm), and longer capsular contact lengths (more than 1 mm) showed higher LNM rates. The model exhibited AUCs of 0.733 and 0.771 in the training and validation cohorts respectively, alongside superior calibration and clinical utility. CONCLUSION: This study proposes and substantiates a preoperative predictive model for LNM in patients with PTMC, honing the precision of "low-risk" categorization. This model furnishes clinicians with an invaluable tool for individualized treatment approach, ensuring better management of patients who might be proposed observation or ablative options in the absence of such predictive information.

Prevalence of vitamin D deficiency and associated risk of all-cause and cause-specific mortality among middle-aged and older adults in the United States.

Introduction: The prevalence of vitamin D deficiency varied among populations and regions worldwide. In addition, the association between vitamin D deficiency and health outcomes remained controversial. Our study aimed to investigate the prevalence of vitamin D deficiency and its association with mortality risk among non-institutional middle-aged and older adults in the United States. Method: The study population included 11,119 adult participants aged between 50 and 79 years in the 2007-2016 National Health and Nutrition Examination Survey (NHANES). Vitamin D status was divided as ≤ 30 (severely deficient), 30.1-50 (moderately deficient), 50.1-75 (insufficient), 75.1-100 (sufficient), and > 100 nmol/L (very sufficient). NHANES data were linked to National Death Index to ascertain the survival status and cause of death. Results: The population aged 61.5 years (survey-weighted) and 47.9% were men. Among them, 4.6% were severely vitamin D deficient, 15.2% moderately deficient, and 33.6% insufficient. Individuals with higher vitamin D levels tended to be female, older, white people, non-smoker, non-single, more educated, with higher family income, and lower body mass index. During a median follow-up of 97.0 months, a total of 1,585 participants died (15.9 per 10,000 person-months). The crude analysis showed that vitamin D deficiency, but not vitamin D insufficiency, correlated to higher all-cause mortality risk. The association remained similar after adjusting for potential confounders, showing that vitamin D deficiency (HR: 1.38, 95% CI 1.15-1.66), but not vitamin D insufficiency (HR: 1.03, 95% CI 0.88-1.20), correlated to higher all-cause mortality risk. In addition, we showed that vitamin D deficiency was an independent risk factor for death from pneumonia (HR: 3.82, 95% CI 1.14-12.86) but not from cardiovascular diseases, cancer, or cerebrovascular diseases. Conclusion: In summary, among middle-aged and older adults in the United States, nearly 20% were vitamin D deficient. Vitamin D deficiency, but not vitamin D insufficiency, correlated to increased mortality risk.

Systematic Review and Meta-Analysis on the Effects of Neurofeedback Training of Theta Activity on Working Memory and Episodic Memory in Healthy Population.

The main purpose of this study was to investigate the effects of neurofeedback training (NFT) of theta activity on working memory (WM) and episodic memory (EM) in healthy participants via a systematic review and meta-analysis. A total of 337 articles obtained from electronic databases were assessed; however, only 11 articles met the criteria for meta-analysis after manually screening and eliminating unnecessary studies. A meta-analysis calculating the Hedges' g effect size metric with 95% confidence intervals using random effects models was employed. Heterogeneity was estimated using I2 statistics. Theta NFT is effective in improving memory outcomes, including WM with a Hedges' g of 0.56 [0.10; 1.02] (I2 = 62.9% and p = 0.02), and EM with a Hedges' g of 0.62 [0.13; 1.10] (I2 = 42.04% and p = 0.01). Overall, the results suggest that theta NFT seems to be useful as nonpharmacological/adjunct training to improve WM and EM in healthy participants.