Microbiome-derived indole-3-lactic acid reduces amyloidopathy through aryl-hydrocarbon receptor activation.

Alzheimer's disease (AD) pathogenesis has been associated with the gut microbiome and its metabolites, though the specific mechanisms have remained unclear. In our study, we used a multi-omics approach to identify specific microbial strains and metabolites that could potentially mitigate amyloidopathy in 5xFAD mice, a widely used model for AD research. Among the microbial strains tested, three showed promising results in reducing soluble amyloid-beta (Aß) levels. Plasma metabolomics analysis revealed an enrichment of tryptophan (Trp) and indole-3-lactic acid (ILA) in mice with reduced soluble Aß levels, suggesting a potential preventative role. The administration of a combined treatment of Trp and ILA prevented both Aß accumulation and cognitive impairment in the 5xFAD mice. Our investigation into the mechanism revealed that ILA's effect on reducing Aß levels was mediated through the activation of microglia and astrocytes, facilitated by the aryl hydrocarbon receptor (AhR) signaling pathway. These mechanisms were verified through experiments in 5xFAD mice that included an additional group with the administration of ILA alone, as well as in vitro experiments using an AhR inhibitor. Clinical data analysis revealed a greater abundance of Lactobacillus reuteri in the gut of healthy individuals compared to those at early stages of Aß accumulation or with mild cognitive impairment. Additionally, human post-mortem brain analyses showed an increased expression of genes associated with the AhR signaling pathway in individuals without AD, suggesting a protective effect against AD progression. Our results indicate that ILA from gut microbes could inhibit the progression of amyloidopathy in 5xFAD mice through activation of AhR signaling in the brain.

Microglia Gravitate toward Amyloid Plaques Surrounded by Externalized Phosphatidylserine via TREM2.

Microglia play a crucial role in synaptic elimination by engulfing dystrophic neurons via triggering receptors expressed on myeloid cells 2 (TREM2). They are also involved in the clearance of beta-amyloid (Aß) plaques in Alzheimer's disease (AD); nonetheless, the driving force behind TREM2-mediated phagocytosis of beta-amyloid (Aß) plaques remains unknown. Here, using advanced 2D/3D/4D co-culture systems with loss-of-function mutations in TREM2 (a frameshift mutation engineered in exon 2) brain organoids/microglia/assembloids, it is identified that the clearance of Aß via TREM2 is accelerated by externalized phosphatidylserine (ePtdSer) generated from dystrophic neurons surrounding the Aß plaques. Moreover, it is investigated whether microglia from both sporadic (CRISPR-Cas9-based APOE4 lines) and familial (APPNL-G-F/MAPT double knock-in mice) AD models show reduced levels of TREM2 and lack of phagocytic activity toward ePtdSer-positive Aß plaques. Herein new insight is provided into TREM2-dependent microglial phagocytosis of Aß plaques in the context of the presence of ePtdSer during AD progression.

Immunosuppressive Cyclotides: A Promising Approach for Treating Autoimmune Diseases.

The immune system maintains constant surveillance to prevent the infiltration of both endogenous and exogenous threats into host organisms. The process is regulated by effector immune cells that combat external pathogens and regulatory immune cells that inhibit excessive internal body inflammation, ultimately establishing a state of homeostasis within the body. Disruption to this process could lead to autoimmunity, which is often associated with the malfunction of both T cells and B cells with T cells playing a more major role. A number of therapeutic mediators for autoimmune diseases are available, from conventional disease-modifying drugs to biologic agents and small molecule inhibitors. Recently, ribosomally synthesized peptides, specifically cyclotides from plants are currently attracting more attention as potential autoimmune disease therapeutics due to their decreased toxicity compared to small molecules inhibitors as well as their remarkable stability against a number of factors. This review provides a concise overview of various cyclotides exhibiting immunomodulatory properties and their potential as therapeutic interventions for autoimmune diseases.

Neurotoxic Microglial Activation via IFNγ-Induced Nrf2 Reduction Exacerbating Alzheimer's Disease.

Microglial neuroinflammation appears to be neuroprotective in the early pathological stage, yet neurotoxic, which often precedes neurodegeneration in Alzheimer's disease (AD). However, it remains unclear how the microglial activities transit to the neurotoxic state during AD progression, due to complex neuron-glia interactions. Here, the mechanism of detrimental microgliosis in AD by employing 3D human AD mini-brains, brain tissues of AD patients, and 5XFAD mice is explored. In the human and animal AD models, amyloid-beta (Aß)-overexpressing neurons and reactive astrocytes produce interferon-gamma (IFNγ) and excessive oxidative stress. IFNγ results in the downregulation of mitogen-activated protein kinase (MAPK) and the upregulation of Kelch-like ECH-associated Protein 1 (Keap1) in microglia, which inactivate nuclear factor erythroid-2-related factor 2 (Nrf2) and sensitize microglia to the oxidative stress and induces a proinflammatory microglia via nuclear factor kappa B (NFκB)-axis. The proinflammatory microglia in turn produce neurotoxic nitric oxide and proinflammatory mediators exacerbating synaptic impairment, phosphorylated-tau accumulation, and discernable neuronal loss. Interestingly, recovering Nrf2 in the microglia prevents the activation of proinflammatory microglia and significantly blocks the tauopathy in AD minibrains. Taken together, it is envisioned that IFNγ-driven Nrf2 downregulation in microglia as a key target to ameliorate AD pathology.

Environmental aluminum oxide inducing neurodegeneration in human neurovascular unit with immunity.

Aluminum oxide nanoparticle (AlNP), a ubiquitous neurotoxin highly enriched in air pollution, is often produced as an inevitable byproduct in the manufacturing of industrial products such as cosmetics and metal materials. Meanwhile, ALNP has emerged as a significant public health concern due to its potential association with neurological diseases. However, the studies about the neurotoxic effects of AlNP are limited, partially due to the lack of physiologically relevant human neurovascular unit with innate immunity (hNVUI). Here, we employed our AlNP-treated hNVUI model to investigate the underlying mechanism of AlNP-driven neurodegeneration. First, we validated the penetration of AlNP across a blood-brain barrier (BBB) compartment and found AlNP-derived endothelial cellular senescence through the p16 and p53/p21 pathways. Our study showed that BBB-penetrating AlNP promoted reactive astrocytes, which produced a significant level of reactive oxygen species (ROS). The astrocytic neurotoxic factors caused neuronal damage, including the synaptic impairment, the accumulation of phosphoric-tau proteins, and even neuronal death. Our study suggests that AlNP could be a potential environmental risk factor of neurological disorders mediated by neuroinflammation.

Three-dimensional human neural culture on a chip recapitulating neuroinflammation and neurodegeneration.

Neuroinflammation has either beneficial or detrimental effects, depending on risk factors and neuron-glia interactions in neurological disorders. However, studying neuroinflammation has been challenging due to the complexity of cell-cell interactions and lack of physio-pathologically relevant neuroinflammatory models. Here, we describe our three-dimensional microfluidic multicellular human neural culture model, referred to as a 'brain-on-a-chip' (BoC). This elucidates neuron-glia interactions in a controlled manner and recapitulates pathological signatures of the major neurological disorders: dementia, brain tumor and brain edema. This platform includes a chemotaxis module offering a week-long, stable chemo-gradient compared with the few hours in other chemotaxis models. Additionally, compared with conventional brain models cultured with mixed phenotypes of microglia, our BoC can separate the disease-associated microglia out of heterogeneous population and allow selective neuro-glial engagement in three dimensions. This provides benefits of interpreting the neuro-glia interactions while revealing that the prominent activation of innate immune cells is the risk factor leading to synaptic impairment and neuronal loss, validated in our BoC models of disorders. This protocol describes how to fabricate and implement our human BoC, manipulate in real time and perform end-point analyses. It takes 2 d to set up the device and cell preparations, 1-9 weeks to develop brain models under disease conditions and 2-3 d to carry out analyses. This protocol requires at least 1 month training for researchers with basic molecular biology techniques. Taken together, our human BoCs serve as reliable and valuable platforms to investigate pathological mechanisms involving neuroinflammation and to assess therapeutic strategies modulating neuroinflammation in neurological disorders.

Astrocytic scar restricting glioblastoma via glutamate-MAO-B activity in glioblastoma-microglia assembloid.

BACKGROUND: Glial scar formation is a reactive glial response confining injured regions in a central nervous system. However, it remains challenging to identify key factors formulating glial scar in response to glioblastoma (GBM) due to complex glia-GBM crosstalk. METHODS: Here, we constructed an astrocytic scar enclosing GBM in a human assembloid and a mouse xenograft model. GBM spheroids were preformed and then co-cultured with microglia and astrocytes in 3D Matrigel. For the xenograft model, U87-MG cells were subcutaneously injected to the Balb/C nude female mice. RESULTS: Additional glutamate was released from GBM-microglia assembloid by 3.2-folds compared to GBM alone. The glutamate upregulated astrocytic monoamine oxidase-B (MAO-B) activity and chondroitin sulfate proteoglycans (CSPGs) deposition, forming the astrocytic scar and restricting GBM growth. Attenuating scar formation by the glutamate-MAO-B inhibition increased drug penetration into GBM assembloid, while reducing GBM confinement. CONCLUSIONS: Taken together, our study suggests that astrocytic scar could be a critical modulator in GBM therapeutics.

Bright-Field and Edge-Enhanced Imaging Using an Electrically Tunable Dual-Mode Metalens.

The imaging of microscopic biological samples faces numerous difficulties due to their small feature sizes and low-amplitude contrast. Metalenses have shown great promise in bioimaging as they have access to the complete complex information, which, alongside their extremely small and compact footprint and potential to integrate multiple functionalities into a single device, allow for miniaturized microscopy with exceptional features. Here, we design and experimentally realize a dual-mode metalens integrated with a liquid crystal cell that can be electrically switched between bright-field and edge-enhanced imaging on the millisecond scale. We combine the concepts of geometric and propagation phase to design the dual-mode metalens and physically encode the required phase profiles using hydrogenated amorphous silicon for operation at visible wavelengths. The two distinct metalens phase profiles include (1) a conventional hyperbolic metalens for bright-field imaging and (2) a spiral metalens with a topological charge of +1 for edge-enhanced imaging. We demonstrate the focusing and vortex generation ability of the metalens under different states of circular polarization and prove its use for biological imaging. This work proves a method for in vivo observation and monitoring of the cell response and drug screening within a compact form factor.

In Vitro Tumor Models on Chip and Integrated Microphysiological Analysis Platform (MAP) for Life Sciences and High-Throughput Drug Screening.

The evolution of preclinical in vitro cancer models has led to the emergence of human cancer-on-chip or microphysiological analysis platforms (MAPs). Although it has numerous advantages compared to other models, cancer-on-chip technology still faces several challenges such as the complexity of the tumor microenvironment and integrating multiple organs to be widely accepted in cancer research and therapeutics. In this review, we highlight the advancements in cancer-on-chip technology in recapitulating the vital biological features of various cancer types and their applications in life sciences and high-throughput drug screening. We present advances in reconstituting the tumor microenvironment and modeling cancer stages in breast, brain, and other types of cancer. We also discuss the relevance of MAPs in cancer modeling and precision medicine such as effect of flow on cancer growth and the short culture period compared to clinics. The advanced MAPs provide high-throughput platforms with integrated biosensors to monitor real-time cellular responses applied in drug development. We envision that the integrated cancer MAPs has a promising future with regard to cancer research, including cancer biology, drug discovery, and personalized medicine.

Nanomedicine for advanced cancer immunotherapy.

Immunotherapy has emerged as a powerful strategy for liquid tumors to overcome the limitations of conventional cancer therapies. The nanomedical delivery system offers the possibility of enhancing cancer immunotherapy and expanding it to solid tumors. Here, we discuss the applications of medical nanoparticles to improve the efficacy of immunotherapy. We first focus on nanomedical particles used in cancer immunotherapy to deliver peptide and mRNA vaccines to the lymph nodes; and the exosome-based therapeutic cancer vaccine. Next, we highlight the applications of nanomedicine in immune checkpoint therapy to prolong the therapeutic effects, enhance tumor-targeting ability, and overcome drug resistance. We also evaluate the roles of nanomedical particles in oncolytic viral treatment, enabling the systemic injection of viruses or oncolytic plasmids/oncotoxic proteins; and virus entry in a receptor-independency manner. Lastly, we focus on nanoparticles in chimeric antigen receptor (CAR) T cell therapy to engineer CAR T cells, enhancing T cell proliferation and infiltration. We envision the nanomedical particles enhancing the therapeutic effects of immunotherapy and revolutionizing cancer therapy in the foreseeable future.

Assessing the multidisciplinary team approaches to placenta accreta spectrum across five institutions within the University of California fetal Consortium (UCfC).

PURPOSE: To describe the multidisciplinary approaches to placenta accreta spectrum (PAS) across five tertiary care centers that comprise the University of California fetal Consortium (UCfC) and to identify potential best practices. MATERIALS AND METHODS: Retrospective review of all cases of pathologically confirmed invasive placenta delivered from 2009 to 2014 at UCfC. Differences in intraoperative management and outcomes based on prenatal suspicion were compared. Interventions assessed included ureteral stent use, intravascular balloon use, anesthetic type, gynecologic oncology (Gyn Onc) involvement, and cell saver use. Intervention variation by institution was also assessed. Analyses were adjusted for final pathologic diagnosis. Chi-square, Fisher's exact, Student's t-test, and Mann-Whitney's U-test were used as appropriate. Binary logistic regression and multivariable linear regression were used to adjust for confounders. RESULTS: One hundred and fifty-one cases of pathologically confirmed invasive placenta were identified, of which 82% (123) were suspected prenatally. There was no correlation between the degree of invasion on prenatal imaging and use of each intervention. Ureteral stents were placed in 33% (41) of cases and did not reduce GU injury. Intravascular balloons were placed in 29% (36) of cases and were associated with shorter OR time (161 versus 236 min, p < .01) and lower estimated blood loss (EBL) (1800 versus 2500 ml, p < .01). General endotracheal anesthesia (GETA) was used in 70% (86). EBL did not differ between GETA and regional anesthesia. Gyn Onc was involved in 58% (71) of cases and EBL adjusted for final pathology was reduced with their involvement (2200 versus 2250 ml, p = .02) while OR time and intraoperative complications did not differ. Cell saver was used in 20% (24) and was associated with longer OR time (296 versus 200 min, p < .01). Use of cell saver was not associated with a difference in EBL or number of units of packed red cells transfused. All analyses were adjusted for pathologic severity of invasion. CONCLUSIONS: Intravascular interventions such as uterine artery balloons and the inclusion of Gynecologic Oncologists as part of a multidisciplinary approach to treating PAS reduce EBL. Additionally, the placement of intravascular balloons may reduce OR time. No significant differences were seen in outcomes when comparing the use of ureteral stents, general anesthesia, or institutions. A team of experienced operators with a standard approach may be more significant than specific practices.

Therapeutic Targeting Strategies for Early- to Late-Staged Alzheimer's Disease.

Alzheimer's disease (AD) is the most common cause of dementia, typically showing progressive neurodegeneration in aging brains. The key signatures of the AD progression are the deposition of amyloid-beta (Aß) peptides, the formation of tau tangles, and the induction of detrimental neuroinflammation leading to neuronal loss. However, conventional pharmacotherapeutic options are merely relying on the alleviation of symptoms that are limited to mild to moderate AD patients. Moreover, some of these medicines discontinued to use due to either the insignificant effectiveness in improving the cognitive impairment or the adverse side effects worsening essential bodily functions. One of the reasons for the failure is the lack of knowledge on the underlying mechanisms that can accurately explain the major causes of the AD progression correlating to the severity of AD. Therefore, there is an urgent need for the better understanding of AD pathogenesis and the development of the disease-modifying treatments, particularly for severe and late-onset AD, which have not been covered thoroughly. Here, we review the underlying mechanisms of AD progression, which have been employed for the currently established therapeutic strategies. We believe this will further spur the discovery of a novel disease-modifying treatment for mild to severe, as well as early- to late-onset, AD.

Development of the Modified Ocimum gratissimum Seeds for Orally Disintegrating Tablets.

BACKGROUND: Natural materials have been encouraged in controlled drug release and improved drug bioavailability. OBJECTIVE: This study aimed to develop a modification process for the use of a natural material, Ocimum gratissimum seeds (OGS), in Orally Disintegrating Tablets (ODTs). METHODS: The OGS was investigated with four different modification processes including only milling, swelling, swelling/milling, and swelling/milling/incubation. The ODTs containing the modified OGS as a disintegrant were prepared by the wet granulation method. Furthermore, an evaluation to assess parameters of tablets, such as weight variation, hardness, friability, wetting time, disintegration time, drug content, and dissolution studies, was performed. RESULTS: The modification of OGS using the swelling/ milling process resulted in a completion of OGS modification, leading to an ideal wetting time, disintegrating time, and dissolution rate. The OGS concentrations also affected the wetting and disintegrating time with the optimal range of ODTs from 15% to 20%. On the other hand, the modification with the incubation processes varied by temperature and time increased the wetting time and disintegrating time. CONCLUSIONS: The modified OGS demonstrated that it is a potential material with the advantages of cost-effectiveness, non-toxicity and easy manufacture in the preparation of ODTs.

Patient and physician preferences for attributes of biologic medications for severe asthma.

OBJECTIVE: Despite the increased availability of biologic treatments indicated for severe asthma, patient and physician preferences for these medications remains largely unknown. The purpose of this study was to understand perceptions of biologic therapies, barriers to care with biologic medications, and preferences for biologic therapy attributes. METHODS: This mixed-methods study involved quantitative surveys and qualitative telephone interviews with patients and physicians from the United States. Participants described preferences for relevant attributes, and barriers to use of biologic medications. Participants rated, ranked, and indicated importance of preferences for different levels of key attributes including: mode of administration, administration setting, dosing frequency, number of injections, and time to onset of effect. Other attributes unique to each group were also included. RESULTS: A total of 47 patients and 25 physicians participated. Patients ranked out-of-pocket costs, mode of administration, time to onset of efficacy, and administration setting as the most important attributes. Physicians ranked mode of administration, time to onset of efficacy, dosing frequency, and insurance reimbursement/access as most important. Both groups expressed preferences for less frequent administrations (Q8W over Q4W or Q2W) (all P<0.01) and subcutaneous (SC) over intravenous injection (both P<0.0001). Key patient barriers to biologic medications include location of treatment, administration time, scheduling, cost/insurance coverage, number of injections, and mode of administration. Physicians identified patient candidacy, convincing patients, administration setting, mode of administration, cost, and administrative burden as key barriers to initiating therapy; and efficacy, speed of onset, convenience of administration, cost, and patient compliance as barriers to staying on therapy. CONCLUSIONS: Patients and physicians expressed strong preferences for less frequent dosing, SC administration, and faster onset. Cost/insurance coverage and convenience issues were key barriers to use. Increased awareness and understanding of preferences and barriers may be useful in facilitating physician-patient conversations with the goal of individualizing treatment.

Maternal and neonatal outcomes among scheduled versus unscheduled deliveries in women with prenatally diagnosed, pathologically proven placenta accreta.

OBJECTIVE: To evaluate maternal and neonatal outcomes among scheduled versus unscheduled deliveries in cases of prenatally diagnosed, pathologically proven placenta accreta. STUDY DESIGN: Retrospective cohort of placenta accreta cases delivered in five University of California hospitals. RESULTS: Of 151 cases of histopathologically proven placenta accreta, 82% were prenatally diagnosed. Sixty-seven percent of women underwent scheduled deliveries and 33% were unscheduled. There were no differences in demographics between groups except a higher rate of antepartum bleeding in the unscheduled delivery group (81 versus 53%; p = .003). Scheduled deliveries were associated with a later gestational age at delivery (34.6 versus 32.6 weeks; p = .001), lower blood loss (2.0 versus 2.5 l; p = .04), higher birth weight (2488 versus 2010 g; p < .001), shorter postpartum length of stay (4 versus 5 d; p = .03) and neonatal length of stay (12 versus 20 d; p = .005). CONCLUSION: Despite a prenatal diagnosis of placenta accreta, 1/3 of these cases require unscheduled delivery, portending poorer maternal and neonatal outcomes.

Maternal and neonatal outcomes after antenatal corticosteroid administration for PPROM at 32 to 33 6/7 weeks gestational age.

BACKGROUND: Preterm Premature Rupture of Membranes (PPROM) precedes many deliveries and experts agree with expectant management until 34 weeks gestation. However, there is controversy regarding the gestational age (GA) for administration of corticosteroids. STUDY DESIGN: We performed a retrospective cohort study in the University of California Fetal Consortium (UCfC). We searched available charts of singleton pregnancies with PPROM between 32 and 33 6/7 weeks GA. Outcomes from the groups were analyzed. RESULTS: Of 191 women with PPROM at 32 to 33 6/7 weeks, 150 received corticosteroids. The median GA at admission was earlier for the exposed versus unexposed group (32 4/7 versus 33 0/7 weeks, respectively, p = 0.001). The mean GA at delivery in the exposed was 33 2/7 (32 0/7 to 35 0/7) weeks versus 33 5/7 (32 0/7 to 36 1/7) weeks in the unexposed (p = 0.001). There was no difference in chorioamnionitis or RDS. CONCLUSION: In women with PPROM at 32 to 33 6/7 weeks, our data suggests that corticosteroids are associated with similar outcomes despite earlier GA at delivery and no differences in major morbidities. A larger prospective study is needed to determine if the benefit of corticosteroids outweighs the potential risks in PPROM.

Caseness rates and risk factors for depression among Vietnamese cancer patients.

OBJECTIVE: Research suggests that rates of depression among general population samples in Asia may be significantly lower than in much of the rest of the world. However, whether this applies to depression among cancer patients is unclear, which is important to determine in order to identify depression treatment needs among cancer patients in this region. The purpose of the present study was to assess caseness rates of serious depression among general cancer patients in the Southeast Asian nation of Viet Nam. METHOD: A total of 695 adult cancer patients from three hospitals in Da Nang, Viet Nam served as study participants. They were assessed at one time point for (a) demographic and (b) cancer characteristics, and (c) depression symptoms. RESULTS: The overall caseness rate for serious depression was 28%. Although rates of depression in general population samples usually are significantly higher in women than men, rates of depression among men and women did not differ significantly among our cancer patients. Higher levels of depressive symptoms were found, however, as a function of lower patient income and education, occupation, cancer stage, and type of cancer, but not marital status or age. CONCLUSIONS: Caseness rates of depression are significantly elevated by a factor of 10-15 among Vietnamese cancer patients relative to general population epidemiological studies in the same region. Although a number of studies have found that rates of depression tend to be lower in Asian as compared to Western general population samples, depression rates among our Vietnamese cancer patients were similar to those reported among Western cancer patients. This suggests that whatever factors are responsible for the relatively low rates of depression observed in Asian general population samples may not be operating in regards to cancer-related depression. Overall, the value of these findings are not only that they provide information for policy makers in Viet Nam to support depression treatment among cancer patients, but also that they suggest that despite the apparent relatively low overall rates of depression it may be useful for cancer and mental health researchers in the region to conduct similar assessments for their policy makers.

Estimating the burden of fungal disease in Vietnam.

Data regarding the prevalence of fungal infections in Vietnam are limited yet they are likely to occur more frequently as increasingly sophisticated healthcare creates more iatrogenic risk factors. In this study, we sought to estimate baseline incidence and prevalence of selected serious fungal infections for the year 2012. We made estimates with a previously described actuarial method, using reports on the incidence and prevalence of various established risk factors for fungal infections from Vietnam, or similar environments, supplemented by personal communications. Global data were used if local data were unavailable. We estimated 2,352,748 episodes of serious fungal infection occurred in Vietnam in 2012. Frequent conditions included recurrent vaginal candidiasis (3893/100,000 women annually), tinea capitis (457/100,000 annually) and chronic pulmonary aspergillosis (61/100,000/5 year period). We estimated 140 cases of cryptococcal meningitis, 206 of penicilliosis and 608 of Pneumocystis jirovecii pneumonia. This is the first summary of Vietnamese fungal infections. The majority of severe disease is due to Aspergillus species, driven by the high prevalence of pulmonary tuberculosis. The AIDS epidemic highlights opportunistic infections, such as penicilliosis and cryptococcosis, which may complicate immunosuppressive treatments. These estimates provide a useful indication of disease prevalence to inform future research and resource allocation but should be verified by further epidemiological approaches.

Weight gain in pregnancy: does the Institute of Medicine have it right?

OBJECTIVE: We aimed to examine whether women who adhered to Institute of Medicine (IOM) guidelines for gestational weight gain (GWG) had improved perinatal outcomes. STUDY DESIGN: This is a population-based retrospective cohort study of nulliparous women with term singleton vertex births in the United States from 2011 through 2012. Women with medical or obstetric complications were excluded. Prepregnancy body mass index was calculated using reported weight and height. Women were categorized into 4 groups based on GWG and prepregnancy body mass index: (1) weight gain less than, (2) weight gain within, (3) weight gain 1-19 lb in excess of, and (4) weight gain ≥20 lb in excess of the IOM guidelines. The χ(2) test and multivariable logistic regression analysis were used for statistical comparisons. RESULTS: Compared to women who had GWG within the IOM guidelines, women with excessive weight gain, particularly ≥20 lb, were more likely to have adverse maternal outcomes (preeclampsia: adjusted odds ratio [aOR], 2.78; 95% confidence interval [CI], 2.82-2.93; eclampsia: aOR, 2.51; 95% CI, 2.27-2.78; cesarean: aOR, 2.1; 95% CI, 2.14-2.19), blood transfusion (aOR, 1.22; 95% CI, 1.11-1.33), and neonatal outcomes (5-minute Apgar <4: aOR, 1.22; 95% CI, 1.14-1.31; ventilation use >6 hours: aOR, 1.24; 95% CI, 1.15-1.33; seizure: aOR, 1.53; 95% CI, 1.24-1.89). Women who gained less than IOM guidelines had lower risks of hypertensive disorders of pregnancy and obstetric interventions but were more likely to have small-for-gestational-age neonates (aOR, 1.55; 95% CI, 1.52-1.59). CONCLUSION: Women whose GWG is in excess of IOM guidelines have higher risk of adverse maternal and neonatal outcomes, particularly in women with ≥20 lb excess weight gain above guidelines while women who had weight gain below the IOM guidelines were less likely to have maternal morbidity but had higher odds of small for gestational age.