Eliciting a single amino acid change by vaccination generates antibody protection against group 1 and group 2 influenza A viruses.

Broadly neutralizing antibodies (bnAbs) targeting the hemagglutinin (HA) stem of influenza A viruses (IAVs) tend to be effective against either group 1 or group 2 viral diversity. In rarer cases, intergroup protective bnAbs can be generated by human antibody paratopes that accommodate the conserved glycan differences between the group 1 and group 2 stems. We applied germline-engaging nanoparticle immunogens to elicit a class of cross-group bnAbs from physiological precursor frequency within a humanized mouse model. Cross-group protection depended on the presence of the human bnAb precursors within the B cell repertoire, and the vaccine-expanded antibodies enriched for an N55T substitution in the CDRH2 loop, a hallmark of the bnAb class. Structurally, this single mutation introduced a flexible fulcrum to accommodate glycosylation differences and could alone enable cross-group protection. Thus, broad IAV immunity can be expanded from the germline repertoire via minimal antigenic input and an exceptionally simple antibody development pathway.

Type 2 vomeronasal receptor-A4 subfamily: Potential predator sensors in mice.

Sensory signals detected by olfactory sensory organs are critical regulators of animal behavior. An accessory olfactory organ, the vomeronasal organ, detects cues from other animals and plays a pivotal role in intra- and inter-species interactions in mice. However, how ethologically relevant cues control mouse behavior through approximately 350 vomeronasal sensory receptor proteins largely remains elusive. The type 2 vomeronasal receptor-A4 (V2R-A4) subfamily members have been repeatedly detected from vomeronasal sensory neurons responsive to predator cues, suggesting a potential role of this receptor subfamily as a sensor for predators. This review focuses on this intriguing subfamily, delving into its receptor functions and genetic characteristics.

Early-life house dust mite aeroallergen exposure augments cigarette smoke-induced myeloid inflammation and emphysema in mice.

BACKGROUND: Longitudinal studies have identified childhood asthma as a risk factor for obstructive pulmonary disease (COPD) and asthma-COPD overlap (ACO) where persistent airflow limitation can develop more aggressively. However, a causal link between childhood asthma and COPD/ACO remains to be established. Our study aimed to model the natural history of childhood asthma and COPD and to investigate the cellular/molecular mechanisms that drive disease progression. METHODS: Allergic airways disease was established in three-week-old young C57BL/6 mice using house dust mite (HDM) extract. Mice were subsequently exposed to cigarette smoke (CS) and HDM for 8 weeks. Airspace enlargement (emphysema) was measured by the mean linear intercept method. Flow cytometry was utilised to phenotype lung immune cells. Bulk RNA-sequencing was performed on lung tissue. Volatile organic compounds (VOCs) in bronchoalveolar lavage-fluid were analysed to screen for disease-specific biomarkers. RESULTS: Chronic CS exposure induced emphysema that was significantly augmented by HDM challenge. Increased emphysematous changes were associated with more abundant immune cell lung infiltration consisting of neutrophils, interstitial macrophages, eosinophils and lymphocytes. Transcriptomic analyses identified a gene signature where disease-specific changes induced by HDM or CS alone were conserved in the HDM-CS group, and further revealed an enrichment of Mmp12, Il33 and Il13, and gene expression consistent with greater expansion of alternatively activated macrophages. VOC analysis also identified four compounds increased by CS exposure that were paradoxically reduced in the HDM-CS group. CONCLUSIONS: Early-life allergic airways disease worsened emphysematous lung pathology in CS-exposed mice and markedly alters the lung transcriptome.

Temperature-related emergency injury visits in Hanoi, Vietnam.

BACKGROUND: The short-term association between increasing temperatures and injury has been described in high-income countries, but less is known for low-income and-middle-income countries, including Vietnam. METHODS: We used emergency injury visits (EIV) data for 2017-2019 from 733 hospitals and clinics in Hanoi, Vietnam to examine the effects of daily temperature on EIV. Time-series analysis with quasi-Poisson models was used to estimate a linear relative risk increase (RRI) for overall populations and ones stratified by age and sex. Exposure-response curves estimated non-linear associations as an RR between daily temperature and injury. Models were adjusted for the day of week, holidays, daily relative humidity, daily particulate matter, and long-term and seasonal trends. RESULTS AND CONCLUSIONS: A total of 39 313 EIV were recorded averaging 36 injuries daily. Injuries more likely occurred in males and those aged 15-44, and aged 44-60. For linear effects, a 5°C increase in same day mean temperature was associated with an overall increased EIV (RRI 4.8; 95% CI 2.3 to 7.3) with males (RRI 5.9; 95% CI 3.0 to 8.9) experiencing a greater effect than females (RRI 3.0; 95% CI -0.5 to 6.5). Non-linear effects showed an increase in EIV at higher temperatures compared with the threshold temperature of 15°C, with the greatest effect at 33°C (RR 1.3; 95% CI 1.2 to 1.6). Further research to investigate temperature-injury among different populations and by the cause of injury is warranted.

Continuity of primary care for type 2 diabetes and hypertension and its association with health outcomes and disease control: insights from Central Vietnam.

BACKGROUND: Vietnam is undergoing a rapid epidemiological transition with a considerable burden of non-communicable diseases (NCDs), especially hypertension and diabetes (T2DM). Continuity of care (COC) is widely acknowledged as a benchmark for an efficient health system. This study aimed to determine the COC level for hypertension and T2DM within and across care levels and to investigate its associations with health outcomes and disease control. METHODS: A cross-sectional study was conducted on 602 people with T2DM and/or hypertension managed in primary care settings. We utilized both the Nijmegen continuity of care questionnaire (NCQ) and the Bice - Boxerman continuity of care index (COCI) to comprehensively measure three domains of COC: interpersonal, informational, and management continuity. ANOVA, paired-sample t-test, and bivariate and multivariable logistic regression analysis were performed to examine the predictors of COC. RESULTS: Mean values of COC indices were: NCQ: 3.59 and COCI: 0.77. The proportion of people with low NCQ levels was 68.8%, and that with low COCI levels was 47.3%. Primary care offered higher informational continuity than specialists (p < 0.01); management continuity was higher within the primary care team than between primary and specialist care (p < 0.001). Gender, living areas, hospital admission and emergency department encounters, frequency of health visits, disease duration, blood pressure and blood glucose levels, and disease control were demonstrated to be statistically associated with higher levels of COC. CONCLUSIONS: Continuity of primary care is not sufficiently achieved for hypertension and diabetes mellitus in Vietnam. Strengthening robust primary care services, improving the collaboration between healthcare providers through multidisciplinary team-based care and integrated care approach, and promoting patient education programs and shared decision-making interventions are priorities to improve COC for chronic care.

Barriers to and facilitators of user engagement with web-based mental health interventions in young people: a systematic review.

Many young people (YP) are diagnosed with mental illnesses and require support. Web-based mental health interventions (W-MHIs) have been increasingly utilized by YP, healthcare providers, and parents due to reasons including convenience and anonymity. W-MHIs are effective in improving mental health in YP. However, real-world engagement with W-MHIs remains low. Therefore, understanding barriers/facilitators of user engagement with W-MHIs is necessary to promote W-MHIs and help users gain optimal benefits through higher engagement. This review aims to identify barriers/facilitators of user engagement with W-MHIs in YP aged 10-24 years. A systematic search of five databases for English language, peer-reviewed publications was conducted between January 2010 and February 2023. Studies examining factors influencing user engagement with W-MHIs, described as barriers or facilitators, were included. Study quality was assessed using the Mixed Methods Appraisal Tool. A narrative synthesis was performed. Of 4088 articles identified, 69 studies were included. Barriers/facilitators were reported by young people (63 studies), providers (17 studies), and parents/caregivers (8 studies). YP perceived that usefulness and connectedness were the most common facilitators, whereas low-perceived need was the most reported barrier. Both providers and parents reported that perceived usefulness for YP was the most common facilitator, whereas concerns about program effectiveness and privacy were noted as barriers. This review found that program- and individual-related factors were important determinants of engagement with W-MHIs. This review provides guidance on the future design and development of new interventions, narrowing the gap between existing W-MHIs and unmet needs of users.

Unleashing the power of boron: enhancing nitrogen reduction reaction through defective ReS2 monolayers.

Density functional theory (DFT) calculations were utilized to investigate the electrocatalytic potential of single boron (B) atom doping in defective ReS2 monolayers as an active site. Our investigation revealed that B-doped defective ReS2, containing S and S-Re-S defects, demonstrated remarkable conductivity, and emerged as an exceptionally active catalyst for nitrogen reduction reactions (NRR), exhibiting limiting potentials of 0.63 and 0.53 V, respectively. For both cases, we determined the potential by examining the hydrogenation of adsorbed N2* to N2H*. Although the competing hydrogen evolution reaction (HER) process appeared dominant in the S-Re-S defect case, its impact was minimal. The outstanding NRR performance can be ascribed to the robust chemical interactions between B and N atoms. The adsorption of N2 on B weakens the N-N bond, thereby facilitating the formation of NH3. Moreover, we verified the selectivity and stability of the catalysts for NRR. Our findings indicate that B-doped defective ReS2 monolayers hold considerable promise for electrocatalysis in a variety of applications.

Detection of triclosan using 2-domain hemoglobin promoter of Daphnia magna.

Triclosan has been widely used as an antimicrobial agent. However, triclosan was found to cause toxicity, including muscle contraction disturbances, carcinogenesis, and endocrine disorders. In addition, it was found to affect central nervous system function adversely and even have ototoxic effects. Conventional methods for detecting such triclosan can be performed easily. However, the conventional detection methods are inadequate in precisely reflecting the impact of toxic substances on stressed organisms. Therefore, a test model for the toxic environment at the molecular level through the organism is needed. From that point of view, Daphnia magna is being used as a ubiquitous model. D. magna has the advantages of easy cultivation, a short lifespan and high reproductive capacity, and high sensitivity to chemicals. Therefore, the protein expression pattern of D. magna that appear in response to chemicals can be utilized as biomarkers for detecting specific chemicals. In this study, we characterized the proteomic response of D. magna following triclosan exposure via two-dimensional (2D) gel electrophoresis. As a result, we confirmed that triclosan exposure completely suppressed D. magna 2-domain hemoglobin protein and evaluated this protein as a biomarker for triclosan detection. We constructed the HeLa cells in which the GFP gene was controlled by D. magna 2-domain hemoglobin promoter, which under normal conditions, expressed GFP, but upon triclosan exposure, suppressed GFP expression. Consequently, we consider that the HeLa cells containing the pBABE-HBF3-GFP plasmid developed in this study can be used as novel biomarkers for triclosan detection.

Transcriptional readout of neuronal activity via an engineered Ca2+-activated protease.

Molecular integrators, in contrast to real-time indicators, convert transient cellular events into stable signals that can be exploited for imaging, selection, molecular characterization, or cellular manipulation. Many integrators, however, are designed as complex multicomponent circuits that have limited robustness, especially at high, low, or nonstoichiometric protein expression levels. Here, we report a simplified design of the calcium and light dual integrator FLARE. Single-chain FLARE (scFLARE) is a single polypeptide chain that incorporates a transcription factor, a LOV domain-caged protease cleavage site, and a calcium-activated TEV protease that we designed through structure-guided mutagenesis and screening. We show that scFLARE has greater dynamic range and robustness than first-generation FLARE and can be used in culture as well as in vivo to record patterns of neuronal activation with 10-min temporal resolution.

Detection of Salmonella dublin using the vitellogenin 2 promoter of Daphnia magna.

Salmonella is a well-known bacterium that causes waterborne diseases in humans and primates. The need for test models to detect such pathogens and study the responses of such organisms to induced toxic environments is vital. Daphnia magna has been ubiquitously used in aquatic life monitoring for decades because of outstanding properties, such as facile cultivation, short lifespan, and high reproductive capacity. In this study, the proteomic response of D. magna exposed to four Salmonella strains (Salmonella dublin, Salmonella enteritidis, Salmonella enterica, and Salmonella typhimurium) was characterized. As indicated by two-dimensional gel electrophoresis, vitellogenin fused with superoxide dismutase was completely suppressed under exposure to S. dublin. Thus, we evaluated the feasibility of using the vitellogenin 2 gene as a biomarker for S. dublin detection, particularly in providing rapid, visual detection through fluorescent signals. Accordingly, the applicability of the HeLa cells transfected with pBABE-Vtg2B-H2B-GFP as a biomarker for the detection of S. dublin was evaluated, and it was confirmed that the fluorescence signal decreased only when S. dublin was treated. Therefore, such HeLa cells can be utilized as a novel biomarker for detecting S. dublin.

Yeast vacuolar enzymes as novel hatching inhibitors for aquatic organisms, Daphnia magna and Danio rerio eggs.

Concerns over the spread of non-native species in aquatic environments have led to the need for effective methods to prevent and control their spread while protecting native species. This study investigated the potential of yeast vacuolar enzymes as a natural hatching inhibitor for controlling aquatic organisms. Hatching experiments with Daphnia magna eggs demonstrated that exposure to yeast vacuole enzymes inhibited hatching in a concentration-dependent manner, suggesting their potential as an effective inhibitor of egg hatching in aquatic organisms. Interestingly, the protease used for comparative purposes did not inhibit hatching, but instead increased the mortality of hatched D. magna. Additionally, chorionic changes were observed in non-hatched D. magna eggs and zebrafish eggs exposed to yeast vacuole enzymes, suggesting that the enzyme can alter the chorion and interfere with hatching. These findings suggest that yeast vacuolar enzymes may be a promising and natural management tool for controlling the spread of harmful aquatic organisms, and further research is warranted to explore their potential for species-specific control.

Integrin α5 Is Regulated by miR-218-5p in Endothelial Progenitor Cells.

BACKGROUND: Endothelial cell injury is a common nidus of renal injury in patients and consistent with the high prevalence of AKI reported during the coronavirus disease 2019 pandemic. This cell type expresses integrin α5 (ITGA5), which is essential to the Tie2 signaling pathway. The microRNA miR-218-5p is upregulated in endothelial progenitor cells (EPCs) after hypoxia, but microRNA regulation of Tie2 in the EPC lineage is unclear. METHODS: We isolated human kidney-derived EPCs (hkEPCs) and surveyed microRNA target transcripts. A preclinical model of ischemic kidney injury was used to evaluate the effect of hkEPCs on capillary repair. We used a genetic knockout model to evaluate the effect of deleting endogenous expression of miR-218 specifically in angioblasts. RESULTS: After ischemic in vitro preconditioning, miR-218-5p was elevated in hkEPCs. We found miR-218-5p bound to ITGA5 mRNA transcript and decreased ITGA5 protein expression. Phosphorylation of 42/44 MAPK decreased by 73.6% in hkEPCs treated with miR-218-5p. Cells supplemented with miR-218-5p downregulated ITGA5 synthesis and decreased 42/44 MAPK phosphorylation. In a CD309-Cre/miR-218-2-LoxP mammalian model (a conditional knockout mouse model designed to delete pre-miR-218-2 exclusively in CD309+ cells), homozygotes at e18.5 contained avascular glomeruli, whereas heterozygote adults showed susceptibility to kidney injury. Isolated EPCs from the mouse kidney contained high amounts of ITGA5 and showed decreased migratory capacity in three-dimensional cell culture. CONCLUSIONS: These results demonstrate the critical regulatory role of miR-218-5p in kidney EPC migration, a finding that may inform efforts to treat microvascular kidney injury via therapeutic cell delivery.

Vitamin E intake and paraoxonase 1 (PON1) rs662 genetic polymorphism are associated with colorectal cancer risk in a Korean population.

Vitamin E and paraoxonase 1 (PON1) are associated with cancer development. However, their interactive effect on colorectal cancer (CRC) risk is inconclusive. We conducted a case-control study including 1,351 CRC patients and 2,670 controls at the Korean National Cancer Centre (KNCC). There was an inverse association between vitamin E intake and CRC risk (odds ratio (OR) = 0.31; 95% confidence interval (CI) = 0.22-0.42). We identified a reduced CRC risk among individuals with CC genotype of PON1 rs662 polymorphism compared with subjects carrying the T allele (OR = 0.74; 95% CI = 0.61-0.90). The highest interaction between vitamin E intake and PON1 rs662 variants was significant for the subjects carrying the CC genotype (p-interaction = 0.014). This study provided further supporting evidence that vitamin E intake is associated with lower odds of CRC. Furthermore, the activity of vitamin E is strengthened among individuals carrying C allele of the PON1 rs662 polymorphism.

Biological Characterization and Genomic Analysis of Novel Phages DLDT_So2 and BHDT_So9 Against Pseudomonas solanacearum, an Infectious Agent in Tomato in Vietnam.

Tomato (Solanum lycopersicum L.) is an important grown vegetable in Vietnam. Bacterial wilt caused by Pseudomonas solanacearum has been considered to be an important disease resulting in a harvest loss up to 90% and significant economic loss to farmers. In this study, two bacteriophages DLDT_So2 and BHDT_So9 specific to P. solanacearum were isolated. Morphological analysis indicated that DLDT_So2 and BHDT_So9 had podovirus morphology and were classified into Autographiviridae family. The latent period and burst size of DLDT_So2 was found to be approximately 120 min and 20.0 ± 2.4 virions per infected cell. Meanwhile, the latent period of BHDT_So9 was 140 min with a burst size of 11.5 ± 2.8 virions per infected cell. Of the 23 bacterial strains tested, the phages infected 7/11 strains of P. solanacearum and none of the other bacteria tested were susceptible to the phages. Stability of the phages at different temperatures, pHs, solvents was also investigated. The genomes of DLDT_So2 and BHDT_So9 are 41,341 bp and 41,296 bp and long with a total GC content of 63%, contains 48 and 46 predicted protein-encoding CDSs. No virulence or antibiotic resistance genes were found in the genomes, suggesting they would be useful biocontrol agents against P. solanacearum. Classification of the phage using average nucleotide identity, phylogenetic analysis was also carried out. The two phages represented new species when they had overall average nucleotide identity of < 95%. This is first report of the isolation and characterization of P. solanacearum-specific phages from tomato farms in Vietnam. Supplementary Information: The online version contains supplementary material available at 10.1007/s12088-023-01090-9.

Fusarium solani PQF9 Isolated from Podocarpus pilgeri Growing in Vietnam as a New Producer of Paclitaxel.

Endophytic fungi are known as an alternative promising source of anticancer drug, paclitaxel, however fungi inhabiting in medicinal plant Podocarpus pilgeri and their paclitaxel production have not been reported to date. In the present study, a total of 15 culturable fungi classified into 5 genera, were successfully recovered from P. pilgeri collected in Vietnam. Screening fungal dichloromethane extracts for anticancer activity revealed that only PQF9 extract displayed potent inhibitory effects on A549 and MCF7 cancer cell lines with IC50 values of 33.9 ± 2.3 µg/mL and 43.5 ± 1.7 µg/mL, respectively. Through PCR-based molecular screening, the isolate PQF9 was found to possess 3 key genes involved in paclitaxel biosynthesis. Importantly, high-performance liquid chromatography quantification showed that fungal isolate PQF9 was able to produce 18.2 µg/L paclitaxel. The paclitaxel-producing fungus was identified as Fusarium solani PQF9 based on morphological and molecular phylogenetic analysis. Intensive investigations by chromatographic methods and spectroscopic analyses confirmed the presence of paclitaxel along with tyrosol and uracil. The pure paclitaxel had an IC50 value of 80.8 ± 9.4 and 67.9 ± 7.0 nM by using cell viability assay on A549 lung and MCF7 breast cancer cells. In addition, tyrosol exhibited strong antioxidant activity by scavenging 2, 2-diphenyl-picrylhydrazyl (DPPH) (IC50 5.1 ± 0.2 mM) and hydroxyl radical (IC50 3.6 ± 0.1 mM). In contrast, no biological activity was observed for uracil. Thus, the paclitaxel-producing fungus F. solani PQF9 could serve as a new material for large-scale production and deciphering paclitaxel biosynthesis. Supplementary Information: The online version contains supplementary material available at 10.1007/s12088-023-01119-z.

Recent strategies and tactics for the enantioselective total syntheses of cyclolignan natural products.

Covering: 2000 to 2021Lignan natural products are found in many different plant species and possess numerous useful biological properties, such as anti-inflammatory, antiviral, antioxidant, antibacterial, and antitumor activities. Their utility in both traditional and conventional medicine, coupled with their structural diversity has made them popular synthetic targets over many decades. This review specifically addresses the cyclolignan subclass of the family, which possess both a C8-C8' and a C2-C7' linkage between two different phenylpropene units. We present a comprehensive overview of the diverse strategies employed by chemists to achieve enantioselective total syntheses of cyclolignans covering: 2000 to 2021.

Oral desensitization therapy for peanut allergy induces dynamic changes in peanut-specific immune responses.

BACKGROUND: The PALISADE study, an international, phase 3 trial of peanut oral immunotherapy (POIT) with AR101, resulted in desensitization in children and adolescents who were highly allergic to peanut. An improved understanding of the immune mechanism induced in response to food allergen immunotherapy would enable more informed and effective therapeutic strategies. Our main purpose was to examine the immunological changes in blood samples from a subset of peanut-allergic individuals undergoing oral desensitization immunotherapy with AR101. METHODS: Blood samples obtained as part of enrollment screening and at multiple time points during PALISADE study were used to assess basophil and CD4+ T-cell reactivity to peanut. RESULTS: The absence of clinical reactivity to the entry double-blinded placebo-controlled peanut challenge (DBPCFC) was accompanied by a significantly lower basophil sensitivity and T-cell reactivity to peanut compared with DBPCFC reactors. At baseline, peanut-reactive TH2A cells were observed in many but not all peanut-allergic patients and their level in peripheral blood correlates with T-cell reactivity to peanut and with serum peanut-specific IgE and IgG4 levels. POIT reshaped circulating peanut-reactive T-cell responses in a subset-dependent manner. Changes in basophil and T-cell responses to peanut closely paralleled clinical benefits to AR101 therapy and resemble responses in those with lower clinical sensitivity to peanut. However, no difference in peanut-reactive Treg cell frequency was observed between groups. CONCLUSION: Oral desensitization therapy with AR101 leads to decreased basophil sensitivity to peanut and reshapes peanut-reactive T effector cell responses supporting its potential as an immunomodulatory therapy.

Systems scale interactive exploration reveals quantitative and qualitative differences in response to influenza and pneumococcal vaccines.

Systems immunology approaches were employed to investigate innate and adaptive immune responses to influenza and pneumococcal vaccines. These two non-live vaccines show different magnitudes of transcriptional responses at different time points after vaccination. Software solutions were developed to explore correlates of vaccine efficacy measured as antibody titers at day 28. These enabled a further dissection of transcriptional responses. Thus, the innate response, measured within hours in the peripheral blood, was dominated by an interferon transcriptional signature after influenza vaccination and by an inflammation signature after pneumococcal vaccination. Day 7 plasmablast responses induced by both vaccines was more pronounced after pneumococcal vaccination. Together, these results suggest that comparing global immune responses elicited by different vaccines will be critical to our understanding of the immune mechanisms underpinning successful vaccination.

Chiral Inversion of 2-Arylpropionic Acid Enantiomers under Anaerobic Conditions.

This work examined the chiral inversion of 2-arylpropionic acids (2-APAs) under anaerobic conditions and the associated microbial community. The anaerobic condition was simulated by two identical anaerobic digesters. Each digester was fed with the substrate containing 11 either pure (R)- or pure (S)-2-APA enantiomers. Chiral inversion was evidenced by the concentration increase of the other enantiomer in the digestate and the changes in the enantiomeric fraction between the two enantiomers. Both digesters showed similar and poor removal of 2-APAs (≤30%, except for naproxen) and diverse chiral inversion behaviors under anaerobic conditions. Four compounds exhibited (S → R) unidirectional inversion [flurbiprofen, ketoprofen, naproxen, and 2-(4-tert-butylphenyl)propionic acid], and the remaining seven compounds showed bidirectional inversion. Several aerobic and facultative anaerobic bacterial genera (Candidatus Microthrix, Rhodococcus, Mycobacterium, Gordonia, and Sphingobium) were identified in both digesters and predicted to harbor the 2-arylpropionyl-CoA epimerase (enzyme involved in chiral inversion) encoding gene. These genera presented at low abundances, <0.5% in the digester dosed with (R)-2-APAs and <0.2% in the digester dosed with (S)-2-APAs. The low abundances of these genera explain the limited extent of chiral inversion observed in this study.

Periodontitis and Preeclampsia in Pregnancy: A Systematic Review and Meta-Analysis.

OBJECTIVES: A conflicting body of evidence suggests localized periodontal inflammation spreads systemically during pregnancy inducing adverse pregnancy outcomes. This systematic review and meta-analysis aim to specifically evaluate the relationship between periodontitis and preeclampsia. METHODS: Electronic searches were carried out in Medline, Pubmed, Embase, Lilacs, Cochrane Controlled Clinical Trial Register, CINAHL, ClinicalTrials.gov, and Google Scholar with no restrictions on the year of publication. We identified and selected observational case-control and cohort studies that analyzed the association between periodontal disease and preeclampsia. This meta-analysis was conducted following the PRISMA checklist and MOOSE checklist. Pooled odds ratios, mean difference, and 95% confidence intervals were calculated using the random effect model. Heterogeneity was tested with Cochran's Q statistic. RESULTS: Thirty studies including six cohort- and twenty-four case-control studies were selected. Periodontitis was significantly associated with increased risk for preeclampsia (OR 3.18, 95% CI 2.26 - 4.48, p < 0.00001), especially in a subgroup analysis including cohort studies (OR 4.19, 95% CI 2.23 - 7.87, p < 0.00001). The association was even stronger in a subgroup analysis with lower-middle-income countries (OR 6.70, 95% CI 2.61 - 17.19, p < 0.0001). CONCLUSIONS: Periodontitis appears as a significant risk factor for preeclampsia, which might be even more pronounced in lower-middle-income countries. Future studies to investigate if maternal amelioration of periodontitis prevents preeclampsia might be warranted.