Dronedarone Enhances the Antibacterial Activity of Polymyxin B and Inhibits the Quorum Sensing System by Interacting with LuxS.

Quorum sensing (QS) is considered an appealing target for interference with bacterial infections. ß-Adrenergic blockers are promising anti-QS agents but do not have antibacterial activity. We assessed the potential ability of adrenergic receptor inhibitors to enhance the antibacterial activity of polymyxin B (PB) against Klebsiella pneumoniae and determined that dronedarone has the most potent activity both in vitro and in vivo. We found that dronedarone increases the thermal stability of LuxS, decreases the production of AI-2, and affects the biofilm formation of K. pneumoniae. We also identified the direct binding of dronedarone to LuxS. However, the mechanism by which dronedarone enhances the antibacterial activity of PB has not been elucidated and is worthy of further exploration. Our study provides a basis for the future development of drug combination regimens.

Evaluation of Stability, Inactivation, and Disinfection Effectiveness of Mpox Virus.

BACKGROUND: Mpox virus (MPXV) infections have increased in many countries since May 2022, increasing demand for diagnostic tests and research on the virus. To ensure personnel safety, appropriate and reliable measures are needed to disinfect and inactivate infectious samples; Methods: We evaluated the stability of infectious MPXV cultures stored at different temperatures and through freeze-thaw cycles. Heat physical treatment (56 °C, 70 °C, 95 °C), chemical treatment (beta-propiolactone (BPL)) and two commercialized disinfectants (Micro-Chem Plus (MCP) and ethanol) were tested against infectious MPXV cultures; Results: The results indicated that MPXV stability increases with lower temperatures. The MPXV titer was stable within three freeze-thaw cycles and only decreased by 1.04 log10 (lg) 50% cell culture infective dose (CCID50) per milliliter (12.44%) after twelve cycles. MPXV could be effectively inactivated at 56 °C for 40 min, 70 °C for 10 min, and 95 °C for 5 min. For BPL inactivation, a 1:1000 volume ratio (BPL:virus) could also effectively inactivate MPXV. A total of 2% or 5% MCP and 75% ethanol treated with MPXV for at least 1 min could reduce >4.25 lg; Conclusions: MPXV shows high stability to temperature and freeze-thaw. Heat and BPL treatments are effective for the inactivation of MPXV, while MCP and ethanol are effective for disinfection, which could help laboratory staff operate the MPXV under safer conditions and improve operational protocols.

Virological Characteristics of Five SARS-CoV-2 Variants, Including Beta, Delta and Omicron BA.1, BA.2, BA.5.

SARS-CoV-2 variants of concern (VOCs) show increasing transmissibility and infectivity and induce substantial injuries to human health and the ecology. Therefore, it is vital to understand the related features for controlling infection. In this study, SARS-CoV-2 WIV04 (prototype) and five VOCs (Beta, Delta, Omicron BA.1, BA.2 and BA.5 variants) were inoculated in Vero cells to observe their growth activities. Apart from evaluating the environmental stability at different temperatures, residual virus titers and infectivity at different temperatures (4 °C, room temperature (RT) and 37 °C) were measured over 7 days. The experiment also assessed the infectivity for different incubation durations. The growth capacity assay suggested that the WIV04, Beta and Delta variants replicated efficiently in Vero cells compared with Omicron Variants, and BA.2 replicated more efficiently in Vero cells than BA.1 and BA.5. In addition, all variants exhibited longer survivals at 4 °C and could remain infectious after 7 days, compared to RT' survival after 5 days and at 37 °C after 1 day. The virus infection assay indicated that the Omicron variant had a weaker ability to infect cells compared to the WIV04, Beta and Delta strains, and a longer infection time was required for these strains, except for BA.2.

Efficacy and Safety of SPN-812 (Extended-Release Viloxazine) in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: A Systematic Review and Meta-Analysis.

BACKGROUND: SPN-812 has been approved for attention-deficit/hyperactivity disorder (ADHD) treatment in children and adolescents. OBJECTIVE: We aimed to analyze the efficacy and safety of different doses of SPN-812 for ADHD pediatric patients of different ages, verify its clinical efficacy, and evaluate its safety. METHODS: Up until 30 August 2023, randomized controlled trials (RCTs) were searched in EMBASE, MEDLINE, the Cochrane Library, and clinicaltrials.gov to evaluate different doses of SPN-812 and a placebo. RESULTS: We pooled 1619 patients from five RCTs with a duration of 6-8 weeks. Patients (6-17 years old) in SPN-812 (100, 200, and 400 mg/d) groups were superior to the control group in all efficacy outcomes with lower attention-deficit/hyperactivity disorder rating scale-5 (ADHD-RS-5), Conners 3-parent short form composite T score (Conners 3-PS), Weiss functional impairment rating scale-parent (WFIRS-P), and increased clinical global impression-improvement (CGI-I) score (both p < 0.05). At the same time, only SPN-812 300 mg/d did not show a significantly high risk of the adverse events (AEs) such as somnolence and decreased appetite (p = 0.09). There was no significant difference between placebo and SPN-812 groups (100, 200, and 400 mg/d) in serious adverse events (SAEs) such as syncope. The subgroup analyses showed that, both in children and adolescents subgroups, SPN-812 showed better efficacy than the placebo. The two age subgroups showed a significantly higher risk of AEs and an insignificant risk of SAEs than the placebo. CONCLUSION: At present, SPN-812 (100, 200, and 400 mg/d) is superior to the corresponding control in efficacy measures. However, the safety problem cannot be ignored.

The enhancement effect of small molecule Lyb24 reveals AzoR as a novel target of polymyxin B.

Given the important role of polymyxin B (PB) in the treatment of drug-resistant Gram-negative bacterial infections, the emergence of PB resistance poses a serious threat to public health. Adjuvant development is a supplementary strategy that can compensate for the lack of novel antibiotics by protecting PB. In this study, we found a small molecule named Lyb24 that showed weak antibacterial activity (minimum inhibitory concentration ≥ 10 µg/ml) but potentiated and revitalized the efficacy of PB against Gram-negative pathogens, including mcr-1- and mgrB-deletion-mediated PB-resistant strains. Our results showed that Lyb24 inhibits the translational levels of genes associated with the modification of lipid A. In addition, Lyb24 increases the permeability, disrupts the integrity and induces the depolarization of the membrane. We further found that both Lyb24 and PB could directly bind to AzoR and inhibit its activity. Structural analysis showed that Lyb24 binds to the isoalloxazine ring of flavin mononucleotide (FMN) through pi-pi stacking and loop η4 of AzoR. A pneumonia model was used to confirm that the activity against clinical PB-resistant Klebsiella pneumoniae was enhanced due to Lyb24 on PB. In conclusion, we provide a potential therapeutic regimen by combining Lyb24 and PB to treat Gram-negative-resistant bacterial infections. Our findings not only explain the synergistic effect of Lyb24, but also expand our knowledge on the mechanism of action of PB.

The assessment on cross immunity with smallpox virus and antiviral drug sensitivity of the isolated mpox virus strain WIBP-MPXV-001 in China.

Since May 2022, human mpox cases have increased unexpectedly in non-endemic countries. The first imported case of human mpox in Hong Kong was reported in September 2022. Here we report the isolation and identification of MPXV from the vesicle swabs of this patient. In this research, the vesicle swabs were inoculated in Vero and Vero E6 cells. In addition to observing cytopathic effects (CPEs) in Vero or Vero E6 cells, the isolated virus was identified as mpox virus (MPXV) using quantitative Real-Time PCR (RT-PCR), transmission electron microscopy, and high-throughput sequencing. The experiment also assessed the cross-protective efficacy of sera from the smallpox vaccinated population and preliminarily assessed the inhibitory effect of anti-smallpox virus drugs against MPXV. CPEs can be observed on Vero E6 cells at 24 h and Vero cells at 48 h. The virus particles could be observed by transmission electron microscope, showing typical orthopoxvirus morphology. In addition, F3L and ATI genes which from MPXV A39R, B2R, HA genes which from orthopoxvirus were confirmed by conventional PCR and Sanger sequencing. The next generation sequencing (NGS) suggests that the MPXV strain belongs to B.1 branch of the West African linage, and has a high identity with the sequence of the 2022 ongoing outbreak. PRNT50 results showed that 26.7% of sera from individuals born before 1981 who had been immunized with smallpox were positive, but no MPXV-neutralizing antibodies were found in sera from individuals born later. All four anti-smallpox virus drugs evaluated demonstrated inhibition of mpox virus.

Heterologous boost with mRNA vaccines against SARS-CoV-2 Delta/Omicron variants following an inactivated whole-virus vaccine.

The coronavirus SARS-CoV-2 has mutated quickly and caused significant global damage. This study characterizes two mRNA vaccines ZSVG-02 (Delta) and ZSVG-02-O (Omicron BA.1), and associating heterologous prime-boost strategy following the prime of a most widely administrated inactivated whole-virus vaccine (BBIBP-CorV). The ZSVG-02-O induces neutralizing antibodies that effectively cross-react with Omicron subvariants. In naïve animals, ZSVG-02 or ZSVG-02-O induce humoral responses skewed to the vaccine's targeting strains, but cellular immune responses cross-react to all variants of concern (VOCs) tested. Following heterologous prime-boost regimes, animals present comparable neutralizing antibody levels and superior protection against Delta and Omicron BA.1variants. Single-boost only generated ancestral and omicron dual-responsive antibodies, probably by "recall" and "reshape" the prime immunity. New Omicron-specific antibody populations, however, appeared only following the second boost with ZSVG-02-O. Overall, our results support a heterologous boost with ZSVG-02-O, providing the best protection against current VOCs in inactivated virus vaccine-primed populations.

Development of a nomogram for severe influenza in previously healthy children: a retrospective cohort study.

OBJECTIVE: We aimed to develop a nomogram to predict the risk of severe influenza in previously healthy children. METHODS: In this retrospective cohort study, we reviewed the clinical data of 1135 previously healthy children infected with influenza who were hospitalized in the Children's Hospital of Soochow University between 1 January 2017 and 30 June 2021. Children were randomly assigned in a 7:3 ratio to a training or validation cohort. In the training cohort, univariate and multivariate logistic regression analyses were used to identify risk factors, and a nomogram was established. The validation cohort was used to evaluate the predictive ability of the model. RESULT: Wheezing rales, neutrophils, procalcitonin > 0.25 ng/mL, Mycoplasma pneumoniae infection, fever, and albumin were selected as predictors. The areas under the curve were 0.725 (95% CI: 0.686-0.765) and 0.721 (95% CI: 0.659-0.784) for the training and validation cohorts, respectively. The calibration curve showed that the nomogram was well calibrated. CONCLUSION: The nomogram may predict the risk of severe influenza in previously healthy children.

Pyrimirhodomyrtone inhibits Staphylococcus aureus by affecting the activity of NagA.

The epidemic of methicillin-resistant Staphylococcus aureus (MRSA) infections has created a critical health threat. The drug resistance of MRSA makes the development of drugs with new modes of action particularly urgent. In this study, we found that a natural product derivative pyrimirhodomyrtone (PRM) exerted antibacterial activity against S. aureus, including MRSA, both in vitro and in vivo. Genetic and biochemical studies revealed the interaction between PRM and N-acetylglucosamine-6-phosphate deacetylase (NagA) and the inhibitory effect of PRM on its deacetylation activity. We also found that PRM causes depolarization and destroys the integrity of the cell membrane. The elucidation of the antibacterial mechanism will inspire the subsequent development of new anti-MRSA drugs based on PRM.

Development and external validation of a simple nomogram for predicting apnea in children hospitalized with bronchiolitis.

Background: Apnea is one of the most life-threatening complications of bronchiolitis in children. This study aimed to determine early predictors of apnea in children hospitalized with bronchiolitis and develop a simple nomogram to identify patients at risk of apnea. Methods: This retrospective, observational study included children hospitalized with bronchiolitis in two hospitals in China. Demographic and clinical characteristics, laboratory results, pathogens, and pulmonary iconography results were recorded. A training cohort of 759 patients (one hospital) was used to identify early predictors of apnea during hospitalization. The least absolute shrinkage and selection operator (LASSO) regression analysis method was used to optimize variable selection. The nomogram was developed visually based on the variables selected by multivariable logistic regression analysis. Discrimination (concordance index, C-index), calibration, and decision curve analysis (DCA) were used to assess the model performance and clinical effectiveness. Results: A total of 1,372 children hospitalized with bronchiolitis were retrospectively evaluated, 133 (9.69%) of whom had apnea. Apnea was observed in 80 of the 759 patients with bronchiolitis in the training cohort and 53 of the 613 patients in the external validation cohort. Underlying diseases, feeding difficulties, tachypnea, retractions and pulmonary atelectasis in the training cohort were independent risk factors for apnea and were assembled into the nomogram. The nomogram exhibited good discrimination with a C-index of 0.883 (95% CI: 0.839-0.927) and good calibration. The DCA showed that the nomogram was clinically useful in estimating the net benefit to patients. Conclusion: We developed a nomogram that is convenient to use and able to identify the individualized prediction of apnea risk in patients with bronchiolitis. These patients might benefit from early triage and more intensive monitoring.

A cyclic adenosine monophosphate response element-binding protein inhibitor enhances the antibacterial activity of polymyxin B by inhibiting the ATP hydrolyzation activity of CrrB.

The emergence of polymyxin B (PB) resistant Gram-negative bacteria poses an important clinical and public health threat. Antibiotic adjuvants development is a complementary strategy that fills the gap in new antibiotics. Here, we described the discovery of the enhancement capacity of compound 666-15, previously identified as an inhibitor of cyclic adenosine monophosphate response element-binding protein (CREB), on the activity of PB against Klebsiella pneumoniae in vitro and in vivo. Mechanistic studies showed that this compound reduced the transcription and translation levels of genes related to lipid A modification in the presence of PB. We also identified that 666-15 reduces the ATP hydrolyzation activity of CrrB, and P151L mutation mediates the resistance of bacteria to the enhancement of 666-15. Our results demonstrated the potential of 666-15 in clinical application and support the further development of a PB synergist based on this compound.

Astilbin Activates the Reactive Oxidative Species/PPARγ Pathway to Suppress Effector CD4+ T Cell Activities via Direct Binding With Cytochrome P450 1B1.

Astilbin, as a compound of flavonoids, exerts anti-inflammation, antioxidation, and immune-suppression activities. Decreased activation of NF-κB and p38 MAPK and increased activation of SOCS3 and AMPK have been found in astilbin-treated cells. However, what molecules are docked by astilbin to initiate signaling cascades and result in functional changes remains unknown. In the study, we found that astilbin efficiently suppressed TNF-α production and increased CCR9 and CD36 expression of CD4+ T cells. In vivo administration of astilbin repressed the occurrence of type 1 diabetes mellitus in non-obese diabetic mice. The PPARγ/SOCS3, PPARγ/PTEN, and PPARγ/AMPK signaling pathways were substantially activated and played key roles in astilbin-induced downregulation of CD4+ T cell functions. Transcriptome sequencing results confirmed the changes of signaling molecules involved in the immune system, inflammatory responses, and indicated variations of multiple enzymes with oxidant or antioxidant activities. Astilbin directly induced cytoplasmic ROS production of CD4+ T cells ex vivo, but had no effects on mitochondrial ROS and mitochondrial weight. When cellular ROS was depleted, astilbin-treated CD4+ T cells remarkably reversed the expression of TNF-α, IFN-γ, CCR9, CD36, and signaling molecules (PPARγ, PTEN, p-AMPK, and SOCS3). Based on bioinformatics, two P450 enzymes (CYP1B1 and CYP19A1) were selected as candidate receptors for astilbin. CYP1B1 was identified as a real docking protein of astilbin in ROS production by AutoDock Vina software analysis and surface plasmon resonance assay. Collectively, astilbin downregulates effector CD4+ T cell activities via the CYP1B1/ROS/PPARγ pathway, which firmly supports its potential use in the treatment of inflammation.

A d,l-lactate biosensor based on allosteric transcription factor LldR and amplified luminescent proximity homogeneous assay.

Lactate, a hydroxycarboxylic acid commercially produced by microbial fermentation, is widely applied in diverse industrial fields. Lactate exists in two stereoisomeric forms (d-lactate and l-lactate). d-Lactate and l-lactate are often simultaneously present in many biological samples. Therefore, a biosensor able to detect both d- and l-lactate is required but previously unavailable. Herein, an allosteric transcription factor LldR from Pseudomonas aeruginosa PAO1, which responds to both d-lactate and l-lactate, was combined with amplified luminescent proximity homogeneous assay technology to develop a d,l-lactate biosensor. The proposed biosensor was optimized by mutation of DNA sequence in binding site of LldR. The optimized biosensor BLac-6 can accurately detect the concentration of lactate independent on ratio of the two isomers in pending test samples. The biosensor was also tentatively used in quantitative analysis of d-lactate, l-lactate, or d,l-lactate in fermentation samples produced by three recombinant strains of Klebsiella oxytoca. With its desirable properties, the biosensor BLac-6 may be a potential choice for monitoring the concentration of lactate during industrial fermentation.

Disulfiram Enhances the Activity of Polymyxin B Against Klebsiella pneumoniae by Inhibiting Lipid A Modification.

BACKGROUND: The use of antibiotic adjuvants is a complementary strategy to the development of new antibiotics. The essential role of the ArnA dehydrogenase domain (ArnA_DH) in the addition of 4-amino-L-arabinose (L-Ara4N) to lipid A makes it a potential target in polymyxin adjuvant design. PURPOSE: This study aimed to identify a dehydrogenase inhibitor that enhances the antibacterial effect of polymyxin B (PB) and to further understand the mechanism of this drug combination. METHODS: A susceptible K. pneumoniae strain, ATCC13883, was used to screen a dehydrogenase inhibitor library based on 3-(4,5)-dimethylthiazol(-z-y1)-2,5-diphenyltetrazolium bromide (MTT) and chequerboard assays. The protein- and cell-based effects of disulfiram (DSF) on ArnA activity were assessed, and the transcription levels of genes in the arn operon were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR). Lipid A was isolated, and a structural analysis was performed. The cell wall function was evaluated through membrane integrity and bacterial viability assays. The in vivo antibacterial activity was evaluated using a mouse pulmonary infection model. RESULTS: We screened a dehydrogenase inhibitor library and found that the anti-alcoholism drug DSF significantly enhanced the antibacterial activity of PB in vitro and in vivo. The protein-based enzyme activity assay showed that DSF exerted no direct effect on the dehydrogenase activity of ArnA. Treatment with the combination of DSF and PB but not with PB alone decreased both the transcription level of genes in the arn operon and the modification level of lipid A. DSF also strengthened the disruption of the cell membrane integrity of PB. Moreover, the enhanced PB antibacterial activity was effective against clinical PB-resistant strains. CONCLUSION: We identified a new drug combination that can be used to reduce the necessary dosage of PB and overcome PB resistance, and this drug combination has good prospects for clinical application.

Verdinexor, a Selective Inhibitor of Nuclear Exportin 1, Inhibits the Proliferation and Migration of Esophageal Cancer via XPO1/c-Myc/FOSL1 Axis.

Esophageal carcinoma (EC) ranks sixth among cancers in mortality worldwide and effective drugs to reduce EC incidence and mortality are lacking. To explore potential anti-esophageal cancer drugs, we conducted drug screening and discovered that verdinexor, a selective inhibitor of nuclear exportin 1 (XPO1/CRM1), has anti-esophageal cancer effects both in vivo and in vitro. However, the mechanism and role of verdinexor in esophageal cancer remain unknown. In the present study, we observed that verdinexor inhibited the proliferation and migration of EC cells in vitro and suppressed tumor growth in vivo. Additionally, we found that verdinexor induced cleavage of PARP and downregulated XPO1, c-Myc, and FOSL1 expression. RNA-sequence analysis and protein-protein interaction (PPI) analysis revealed that verdinexor regulated the XPO1/c-Myc/FOSL1 axis. The results of immunoprecipitation and proximity ligation assays confirmed that verdinexor disrupted the interaction between XPO1 and c-Myc. Overexpression of c-Myc rescued the inhibition of cell proliferation and cell migration caused by verdinexor. Overexpressed FOSL1 restored the inhibited migration by verdinexor. Taken together, verdinexor inhibited cell proliferation and migration of esophageal cancer via XPO1/c-Myc/FOSL1 axis. Our findings provide a new option for the development of anti-esophageal cancer drugs.

A D-2-hydroxyglutarate biosensor based on specific transcriptional regulator DhdR.

D-2-Hydroxyglutarate (D-2-HG) is a metabolite involved in many physiological metabolic processes. When D-2-HG is aberrantly accumulated due to mutations in isocitrate dehydrogenase or D-2-HG dehydrogenase, it functions in a pro-oncogenic manner and is thus considered a therapeutic target and biomarker in many cancers. In this study, DhdR from Achromobacter denitrificans NBRC 15125 is identified as an allosteric transcriptional factor that negatively regulates D-2-HG dehydrogenase expression and responds to the presence of D-2-HG. Based on the allosteric effect of DhdR, a D-2-HG biosensor is developed by combining DhdR with amplified luminescent proximity homogeneous assay (AlphaScreen) technology. The biosensor is able to detect D-2-HG in serum, urine, and cell culture medium with high specificity and sensitivity. Additionally, this biosensor is used to identify the role of D-2-HG metabolism in lipopolysaccharide biosynthesis of Pseudomonas aeruginosa, demonstrating its broad usages.

A small molecule interacts with pMAC-derived hydroperoxide reductase and enhances the activity of aminoglycosides.

The threat of antimicrobial resistance calls for more efforts in basic science, drug discovery, and clinical development, particularly gram-negative carbapenem-resistant pathogens. We sought to identify novel antibacterial agents against Acinetobacter baumannii ATCC19606 using whole cell-based screening. A small molecule named 6D1 with the chemical structure of 6-fluorobenzo[d]isothiazol-3(2H)-one was identified and exhibited activity against A. baumannii ATCC19606 strain (minimal inhibitory concentration, MIC = 1 mg l-1). The mutation in the plasmid-derived ohrB gene that encodes a peroxidase was identified in spontaneously resistant mutants. Treatment of the bacteria with 6D1 resulted in increased sensitivity to peroxide, such as tert-butyl hydroperoxide. The binding of 6D1 and OhrB was confirmed by surface plasmon resonance. Interestingly, the MIC of kanamycin and gentamicin against spontaneously resistant mutants decreased. Finally, we identified the effect of 6D1 on enhancing the antibacterial activity of kanamycin and gentamicin, including against New Delhi metallo-ß-lactamase (NDM-1)-producing carbapenem-resistant Klebsiella pneumoniae, but not in strains carrying aminoglycosides resistance genes. In this study, we identified a small molecule that suppresses the growth of A. baumannii, interacts with hydroperoxide reductase from A. baumannii ATCC19606 plasmid pMAC, and enhances the antibacterial activity of kanamycin and gentamicin. We propose that peroxidase may be potentially used as a target for aminoglycosides adjuvant development.

Numerical simulations on narrow-linewidth photonic microwave generation based on a QD laser simultaneously subject to optical injection and optical feedback.

Based on a three-level model for quantum dot (QD) lasers, the characteristics of the photonic microwave generated by a QD laser simultaneously subject to optical injection and optical feedback are numerically investigated. First, the performance of the microwave signal generated by an optical injected QD laser operating at period one state are analyzed, and the mappings of the frequency and intensity of the generated microwave in the parameter space of the frequency detuning and injection strength are given, which are roughly similar to those reported experimentally. Next, an optical feedback loop is further introduced to the optically injected QD laser for compressing the linewidth of the microwave signal, and the results demonstrate that the linewidth of the generated microwave can be reduced by at least 1 order of magnitude under suitable feedback parameters. Finally, the effect of the linewidth enhancement factor on the generated microwave signal is analyzed.

Numerical investigations on multi-channel wideband chaotic signal generation by a multi-transverse mode vertical-cavity surface-emitting laser subject to chaotic optical injection.

A multi-channel wideband chaotic signal generation scheme is proposed and numerically investigated based on a slave multi-transverse mode vertical-cavity surface-emitting laser (SL) subject to chaotic optical injection from a master multi-transverse mode vertical-cavity surface-emitting laser (ML) with optical feedback. Taking two low-order transverse modes, LP01 and LP11, as an example for numerical calculations, the simulated results show that under suitable optical feedback both the LP01 and LP11 modes (two-channel) of a ML can be driven into the chaotic states where their bandwidths are relatively narrow at a level about 8 GHz. Further injecting the two chaotic signals into a SL, for the case of the globally chaotic optical injection, the SL can output two-channel chaotic signals with wide bandwidths above 20 GHz under appropriate operation parameters. Moreover, the case of SL with mode-selective chaotic optical injection is also analyzed.

The Effect of Dehydroepiandrosterone (DHEA) Supplementation on IVF or ICSI: A Meta-Analysis of Randomized Controlled Trials.

Introduction A systematic review and meta-analysis were conducted to evaluate the efficacy of dehydroepiandrosterone (DHEA) supplementation in patients with diminished ovarian reserve (DOR) and/or poor ovarian response (POR) who were undergoing in vitro fertilization or intracytoplasmic sperm injection (IVF/ICSI). Patients and Methods We searched the PubMed, EMBASE, Web of Science, and Cochrane Library electronic databases for literature published until July 2018. The analysis included randomized controlled trials (RCTs) of the effects of DHEA versus placebo on IVF or ICSI. Two independent reviewers extracted information from the reports and evaluated the quality of the studies. Overall, we identified nine prospective RCTs involving 833 patients. Results Compared to the controls, patients treated with DHEA exhibited increases in the number of retrieved oocytes (mean difference, 0.91; 95% confidence interval [CI], 0.23 - 1.59; p = 0.009), clinical pregnancy rate (relative risk [RR] = 1.27; 95% CI, 1.01 - 1.61; p = 0.04), and live birth rate (RR, 1.76; 95% CI, 1.17 - 2.63; p = 0.006). However, there was no intergroup difference in the miscarriage rate (RR, 0.37; 95% CI, 0.12 - 1.13; p = 0.08). Conclusion DHEA supplementation improved the outcomes of IVF/ICSI in women with DOR or POR.