Cystatin M/E ameliorates bone resorption through increasing osteoclastic cell estrogen influx.

In multiple myeloma (MM), increased osteoclast differentiation leads to the formation of osteolytic lesions in most MM patients. Bisphosphonates, such as zoledronic acid (ZA), are used to ameliorate bone resorption, but due to risk of serious side effects as well as the lack of repair of existing lesions, novel anti-bone resorption agents are required. Previously, the absence of osteolytic lesions in MM was strongly associated with elevated levels of cystatin M/E (CST6), a cysteine protease inhibitor, secreted by MM cells. In this study, both MM- and ovariectomy (OVX)-induced osteoporotic mouse models were used to compare the effects of recombinant mouse CST6 (rmCst6) and ZA on preventing bone loss. µCT showed that rmCst6 and ZA had similar effects on improving percent bone volume, and inhibited differentiation of non-adherent bone marrow cells into mature osteoclasts. Single-cell RNA sequencing showed that rmCst6 and not ZA treatment reduced bone marrow macrophage percentage in the MM mouse model compared to controls. Protein and mRNA arrays showed that both rmCst6 and ZA significantly inhibit OVX-induced expression of inflammatory cytokines. For OVX mice, ERα protein expression in bone was brought to sham surgery level by only rmCst6 treatments. rmCst6 significantly increased mRNA and protein levels of ERα and significantly increased total intracellular estrogen concentrations for ex vivo osteoclast precursor cell cultures. Based on these results, we conclude that CST6 improves MM or OVX bone loss models by increasing the expression of estrogen receptors as well as the intracellular estrogen concentration in osteoclast precursors, inhibiting their maturation.

Effect of Various Toothpaste Tablets on Gloss and Surface Roughness of Resin-based Composite Materials.

OBJECTIVES: To evaluate the effect of various toothpaste tablets on gloss and surface roughness of resin-based composite. METHODS AND MATERIALS: Sixty-four resin-based composite specimens were divided into four groups of 16 specimens each. Gloss and roughness were measured before and after simulated brushing with three types of toothpaste tablets and one conventional toothpaste: CT: Chewtab Toothpaste Tablets; AT: Anticavity Toothpaste Tablets; HC: Charcoal Toothpaste Tablets; CP: Cavity Protection toothpaste. The Kruskal-- Wallis procedure was performed to compare the differences by groups. Post-hoc comparisons were conducted with Bonferroni corrections (α=0.05). RESULTS: There was a significant drop in gloss for all groups. CT and AT maintained the highest gloss with means of 81.6 GU and 74.1 GU, respectively. The lowest gloss of 24.5 GU was observed for HC. There was a significant increase in roughness for all groups except for CT. CT had the lowest roughness with a mean of 0.034 µm, while HC had the highest roughness with a mean of 0.074 µm. There was a significant correlation between post-brushing gloss and post-brushing roughness (p<0.001, r=-0.884). CONCLUSION: Chewtab Toothpaste Tablets had the least effect on gloss and roughness, while Charcoal Toothpaste Tablets had the most negative effect on the surface properties of resin-based composites.

Phenolic acids prevent sex-steroid deficiency-induced bone loss and bone marrow adipogenesis in mice.

Phenolic acids, such as hippuric acid (HA) and 3-(3-hydroxyphenyl) propionic acid (3-3-PPA), can be produced from microbiome digestion of polyphenols. Previously it was found that HA and 3-3-PPA facilitate bone formation and suppress bone resorption. However, the mechanism of action by which HA and 3-3-PPA protect bone from degeneration is currently unknown. In this report, we present that HA and 3-3-PPA suppression of bone resorption is able to ameliorate bone loss in an ovariectomy (OVX) osteopenic mouse model though not to the extent of Zoledronic acid (ZA). HA and 3-3-PPA treatments were shown to significantly decrease bone marrow adipocyte-like cell formation and inhibited gene expression of key adipogenesis regulator peroxisome proliferator activated receptor gamma (PPARγ) and lipoprotein lipase (Lpl) in bone from OVX mice. In addition, ChIP experiments showed that the association between PPARγ and Lpl promoter region in preadipocyte-like cells was significantly suppressed following HA or 3-3-PPA treatment. Contrasting HA and 3-3-PPA, ZA significantly increased TRAP activity in the area close to growth plate and significantly suppressed bone cell proliferation. These data suggest that phenolics acids such as HA or 3-3-PPA may prevent bone degeneration after OVX through suppression of inflammatory milieu in the bone.

Synthesis of High Sn Content Ge1-x-ySixSny (0.1 < y < 0.22) Semiconductors on Si for MWIR Direct Band Gap Applications.

A systematic effort has been described to grow ternary Ge1-x-ySixSny semiconductors on silicon with high Sn concentrations spanning the 9.5-21.2% range. The ultimate goal is not only to produce direct band gap materials well into the infrared region of the spectrum but also to approach a critical concentration (yc) for which further additions of Si would decrease─rather than increase─the band gap. This counterintuitive behavior is expected as a result of the giant bowing parameter in the compositional dependence of the band gap associated with the presence of Si-Sn pairs. The growth approach in this study was based on a chemical vacuum deposition method that uses Si4H10, Ge3H8, and SnD4 or SnH4 as the sources of Si, Ge, and Sn, respectively. A fixed Si concentration near x = 0.05-0.07 was chosen to focus the exploration of the compositional space. A first family of samples was grown of Ge-buffered Si substrates. For Sn concentrations y < 0.12, it was found that the samples relaxed their mismatch strain in situ during growth, resulting in high Sn content films that had relatively low levels of strain and exhibited photoluminescence signals that demonstrated direct band gap behavior for the first time. The device potential of these materials was also demonstrated by fabricating a prototype photodiode with low dark currents. The optical studies suggest that the above-mentioned critical concentration is close to yc = 0.2. As the growth temperature was lowered in an effort to reach such values, Sn concentrations as high as y = 0.15 were obtained, but the films grew fully strained with compressive levels as high as 1.7%. To increase the Sn concentration beyond y = 0.15, a new strategy was adopted, in which the Ge buffer layer was eliminated, and the ternary alloy was grown directly on Si. The much higher lattice mismatch between the Ge1-x-ySixSny layer and the Si substrate caused strain relaxation right at the film/substrate interface, and the subsequent films grew with much lower levels of strain. This made it possible to lower the growth temperatures even further and achieve a comprehensive series of strained relaxed samples with tunable Sn concentrations as high as y = 0.21 (and beyond). The latter represent the highest Sn contents in crystalline Ge1-x-ySixSny attained to date and reach the desired yc = 0.2 range. The synthesized films exhibited significant thickness, allowing a thorough determination of composition, crystallinity, morphology, and bonding properties, indicating the formation of single-phase single-crystal alloys with random cubic structures. Further work will focus on optimizing the latter samples to explore the optical and electronic properties.

Real options analysis for valuation of climate adaptation pathways with application to transit infrastructure.

Climate change and sea-level rise (SLR) are expected to increase the frequency and intensity of coastal flood events, posing risks to coastal communities and infrastructure. While regional climate adaptation investments can provide substantive flood protection, existing plans often neglect uncertainty in future climate conditions and adaptation performance, consequently neglecting the option value of flexibly implementing proposed projects. Addressing this gap, we develop and employ a generalizable real options analysis (ROA) valuation framework that considers how uncertainty in adaptation project costs, SLR, flood severity, and flood losses inform the full range of adaptation performance outcomes. We further propose and apply a novel, computationally efficient flood loss sampling algorithm to estimate the consequences of randomly arriving coastal flood events. We apply this ROA framework to assess the option value of flexibly timing adaptation investments over time, investigating an adaptation pathway proposed by the City of Boston from the perspective of the regional transit system manager. Our results suggest that flexible implementation can provide significant option value in the near- to mid-term (>30 years), with the highest option values under low-probability, high-consequence scenarios. Our results also suggest adaptation pathway performance in the latter half of the 21st century is most sensitive to uncertainty in SLR, flood loss estimates, and flood frequency, underscoring the importance of uncertainty quantification in the long-term valuation of adaptation investments.

Decreased bone resorption in Ezh2 myeloid cell conditional knockout mouse model.

Osteoclasts derived from hematopoietic stem cells control bone resorption. Identifying novel molecules that can epigenetically regulate osteoclastogenesis is important for developing novel treatments for osteoporosis and other disorders associated with bone deterioration and promoting healthy bone formation. The polycomb group (PcG) protein enhancer of zeste homolog 2 (Ezh2), a histone lysine methyltransferase, is associated with epigenetic regulation of numerous cellular processes, but its involvement in bone cell development and homeostasis is not yet clear. Here, LysM-Cre mice were crossed with Ezh2flox/flox mice to delete Ezh2 in myeloid cell lineage mature macrophages. Conditional knockout of Ezh2 (CKO) in myeloid cell line resulted in significant increases in postnatal bone growth in the first 6 months of life for both male and female mice. For female mice, optimal bone mass was seen for mice with Ezh2 deleted in both chromosomes in a pair (f/f Cre+ ; CKO). For male mice, optimal bone mass was found after deletion of Ezh2 from just one chromosome (f/- Cre+ ) with no difference in bone phenotype between f/- Cre+ and CKO male mice. In addition to the gender-specific difference in bone phenotype, Ezh2 CKO mice had significantly less macrophages (CD11b+) present in the bone marrow compared with control mice as well as significantly more mature osteoblasts and bone formation biomarkers present (P1NP, osteocalcin). Inflammatory array for protein lysed from bone tissue revealed deletion of Ezh2 decreased inflammatory milieu in both male and female mice compared with controls. Unexpectedly, myeloid cell deletion of Ezh2 also increased the number of mature osteoblast present in the bone. Deletion of Ezh2 also led to an increase in gene expression of osteoclast-suppressive genes IRF8, MafB, and Arg1 due to a decrease in the presence of the suppressive H3K27me3 epigenetic mark. These findings suggest that manipulation of Ezh2 expression may be a viable strategy to combat bone resorptive disorders such as osteoporosis or arthritis.

Differential plasma branched-chain amino acid responses following the consumption of Greek-style yogurt and skimmed milk.

We examined postprandial branched-chain amino acid (BCAA), insulin, and glucose responses in blood for 4 h following the consumption of two isonitrogenous doses (2 × 20 g protein) of Greek-style yogurt (GY) and skimmed milk (MILK) in young males. Peak leucine and BCAA concentrations and areas under the curve were greater after GY versus MILK, and time to maximal leucine/BCAA concentrations was similar between conditions. We demonstrated that different protein-matched wholefood dairy products elicit different postprandial aminoacidemic responses.

Computational investigation of α-SiO2 surfaces as a support for Pd.

The properties of a supported metal catalyst depend crucially on the interaction between the active metal and the support. A case in point is Pd supported on silica, Pd/SiO2, which is widely used in oxidation catalysis. There is a need for a broad range of computational models that describe the interaction of Pd with silica surfaces so that active site models can be proposed and tested. In this work, we create well-defined, reproducible, periodic models of SiO2 surfaces and investigate their interaction with Pd using dispersion-corrected DFT. We use crystalline α-SiO2 as a useful starting point for creating and estimating the adsorption properties of metals on SiO2 surfaces, which can represent the specific isolated functional groups present on more complex amorphous silica surfaces. We have modelled α-SiO2 (001), (100) and (101) surfaces containing isolated siloxane and silanol functional groups and estimated their affinity towards the adsorption of Pd atoms regarding an isolated gaseous Pd atom and the fcc Pd solid. This provides additional information on the ease with which Pd can be dispersed on the surfaces in question. From our model, we characterise the surface energies of the α-SiO2 (hkl) surfaces and calculate the geometries of the Pd1/α-SiO2 (hkl) adsorption site on each surface. We estimate that Pd1(g) will prefer to adsorb close to strained four-membered siloxane rings or on a vicinal silanol group of α-SiO2 (101).

Primary Care Patients' and Staff's Perceptions of Self-Rooming as Alternative to Waiting Rooms.

PURPOSE: Most patients are escorted to exam rooms (escorted rooming) although patients directing themselves to their exam room (self-rooming) saves patient and staff time while increasing patient satisfaction. This study assesses patient and staff perceptions after pragmatic implementation of self-rooming. METHODS: In October-December 2020, we surveyed patients and staff in 25 primary care clinics after our institution expanded self-rooming from 4 specially built clinics during the COVID-19 pandemic. Semi-structured surveys asked about rooming process used, rooming process preferred, and perceptions of self-rooming compared with escorted rooming. RESULTS: Most patients (n = 1,561) preferred self-rooming (86%), especially among patients aged <65 years and in family medicine clinics. Few patients felt less welcomed (10.6%), less cared about (6.8%), more isolated (15.6%), more lost/confused (7.6%), or more frustrated (3.2%) with self-rooming compared with escorted rooming. Early-adopter clinics that implemented self-rooming ≤2016 had even lower rates of patients feeling more isolated, lost/confused, or frustrated with self-rooming compared with escorted rooming.Over one-half of staff (n = 241; 180 clinical, 61 nonclinical) preferred self-rooming (59%) and thought most patients liked self-rooming (65.8%), especially among clinical staff and in early adopter clinics (≤2016). Few staff reported worse waiting times for patients (12.4%), medical assistants (MAs) (15.9%), and clinicians (16.4%) or worse crowding in waiting areas (1.7%) and hallways (10.1%). Unlike patient-reported confusion (7.6%), most staff thought self-rooming led to more patient confusion (63.8%), except in early-adopter clinics (44.4%). CONCLUSIONS: Self-rooming is a patient-centered innovation that is also acceptable to staff. We demonstrated that pragmatic implementation is feasible across primary care without expensive technology or specially designed buildings.

Maternal high-fat diet modifies epigenetic marks H3K27me3 and H3K27ac in bone to regulate offspring osteoblastogenesis in mice.

Studies from both humans and animal models indicated that maternal chronic poor-quality diet, especially a high fat diet (HFD), is significantly associated with reduced bone density and childhood fractures in offspring. When previously studied in a rat model, our data suggested that maternal HFD changes epigenetic marks such as DNA methylation and histone modifications to control osteoblast metabolism. In mouse embryonic and postnatal offspring bone samples, a ChIP-sequencing (ChIP-Seq)-based genome-wide method was used to locate the repressive histone mark H3K27me3 (mediated via the polycomb histone methyltransferase, Ezh2) and expressive histone mark H3K27ac (p300/CBP mediated) throughout the genome. Using isolated mouse embryonic cells from foetal calvaria (osteoblast-like cells), H3K27me3 ChIP-Seq showed that 147 gene bodies and 26 gene promoters in HFD embryotic samples had a greater than twofold increase in H3K27me peaks compared to controls. Among the HFD samples, Pthlh and Col2a1 that are important genes playing roles during chondro- and osteogenesis had significantly enriched levels of H3K27me3. Their decreased mRNA expression was confirmed by real-time PCR and standard ChIP analysis, indicating a strong association with Ezh2 mediated H3K27me3 epigenetic changes. Using embryonic calvaria osteoblastic cells and offspring bone samples, H3K27ac ChIP-Seq analysis showed that osteoblast inhibitor genes Tnfaip3 and Twist1 had significantly enriched peaks of H3K27ac in HFD samples compared to controls. Their increased gene expression and association with H3K27ac were also confirmed by real-time PCR and standard ChIP analysis. These findings indicate that chronic maternal HFD changes histone trimethylation and acetylation epigenetic marks to regulate expression of genes controlling osteoblastogenesis.

Exudative Retinal Detachment Following Chimeric Antigen Receptor T-Cell Therapy in Relapsed B-Cell Acute Lymphoblastic Leukemia.

Chimeric antigen receptor (CAR) T-cell therapy has become a novel approach in the treatment of many hematologic malignancies. However, ocular adverse effects have not been well described. This report presents a case of a pediatric patient with relapsed B-cell acute lymphoblastic leukemia with ocular involvement treated with CAR T-cell therapy who developed an exudative retinal detachment likely secondary to an inflammatory response to CAR T-cell therapy. [Ophthalmic Surg Lasers Imaging Retina. 2022;53:113-115.].

Efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with B-cell non-Hodgkin lymphoma.

Patients diagnosed with B-cell non-Hodgkin lymphoma (B-NHL), particularly if recently treated with anti-CD20 antibodies, are at risk of severe COVID-19 disease. Because studies evaluating humoral response to COVID-19 vaccine in these patients are lacking, recommendations regarding vaccination strategy remain unclear. The humoral immune response to BNT162b2 messenger RNA (mRNA) COVID-19 vaccine was evaluated in patients with B-NHL who received 2 vaccine doses 21 days apart and compared with the response in healthy controls. Antibody titer, measured by the Elecsys Anti-SARS-CoV-2S assay, was evaluated 2 to 3 weeks after the second vaccine dose. Patients with B-NHL (n = 149), aggressive B-NHL (a-B-NHL; 47%), or indolent B-NHL (i-B-NHL; 53%) were evaluated. Twenty-eight (19%) were treatment naïve, 37% were actively treated with a rituximab/obinutuzumab (R/Obi)-based induction regimen or R/Obi maintenance, and 44% had last been treated with R/Obi >6 months before vaccination. A seropositive response was achieved in 89%, 7.3%, and 66.7%, respectively, with response rates of 49% in patients with B-NHL vs 98.5% in 65 healthy controls (P < .001). Multivariate analysis revealed that longer time since exposure to R/Obi and absolute lymphocyte count ≥0.9 × 103/µL predicted a positive serological response. Median time to achieve positive serology among anti-CD20 antibody-treated patients was longer in i-B-NHL vs a-B-NHL. The humoral response to BNT162b2 mRNA COVID-19 vaccine is impaired in patients with B-NHL who are undergoing R/Obi treatment. Longer time since exposure to R/Obi is associated with improved response rates to the COVID-19 vaccine. This study is registered at www.clinicaltrials.gov as #NCT04746092.

Hemorrhagic Shock after Neonatal Circumcision: Severe Congenital Factor XIII Deficiency.

A Caucasian male infant born full term via normal spontaneous vaginal delivery was given vitamin K after birth, circumcised on day of life (DOL) 1, and discharged from the nursery on DOL 2. At the time of circumcision, oozing from the surgical site was noted and initially resolved with silver nitrate. Over the next two days, he presented to local emergency rooms multiple times for recurrent bleeding, eventually developing hemorrhagic shock resulting in admission to the neonatal intensive care unit. After extensive work up, he was ultimately diagnosed with severe congenital factor XIII deficiency. Congenital factor XIII deficiency is a rare bleeding disorder characterized by normal prothrombin time (PT) and activated partial thromboplastin time (aPTT) coagulation labs on routine screening, and has a high risk of complications, such as spontaneous intracranial hemorrhage. Although uncommon, when caring for a child with bleeding, physicians must have a high index of suspicion to make this diagnosis in order to initiate proper treatment and start prophylaxis given the risk of morbidity and mortality in untreated patients.

Novel agents for the treatment of lymphomas during pregnancy: A comprehensive literature review.

Lymphoproliferative diseases occurring during pregnancy present unique diagnostic and therapeutic challenges aiming to achieve maternal cure without impairing fetal health, growth, and survival. These goals are further complicated by the fast-paced emergence of novel therapies and their introduction as standard of care, even in newly diagnosed patients. Due to the rarity of hematological malignancies in pregnancy and the exclusion of pregnancy in almost all clinical trials, available data on the fetal effects of novel drugs are limited to animal models and case reports. The current review addresses the entire multidisciplinary team involved in treating pregnant patients with lymphoproliferative diseases. We describe novel agents according to their mechanism of action, and summarize our knowledge of their effects during the gestational period, particularly those associated with fetotoxicity. Therapeutic dilemmas associated with the employment of these new agents are also discussed.

Foveal macular pigment dip in offspring of age-related macular degeneration patients is inversely associated with omega-3 index.

BACKGROUND: Offspring of parent(s) with age-related macular degeneration (AMD) have a 45% lifetime risk of developing the disease. High foveal macular pigment optical density (MPOD) is protective, whereas individuals with a "foveal macular pigment dip" (FMPD) are at increased risk. Shortage of the dietary carotenoids lutein, zeaxanthin as well as fish consumption are reported AMD risk factors. This Early Biomarkers of AMD (EBAMD) study evaluates serum factors that protect foveal MPOD architecture in Caucasian offspring of parent(s) with AMD. METHODS: N = 130 subjects [mean (SD) age 62.8 (8.6) years; 36/94 male/female] were recruited from Scripps Health/ Scripps Memorial Hospital/ Scripps Mericos Eye Institute between 2012 and 2017. Macula pigment 3D topography was evaluated using specular reflectance. Buccal genetic cheek swab, circulating serum dietary carotenoids and long-term RBC omega-3 fatty acid status, as well as common secondary clinical structural and vision function parameters were obtained. RESULTS: 41 % of offspring of AMD parent(s) presented with FMPD. These offspring were about 4 years younger than those without FMPD (controls; P = 0.012) and had thinner foveas (P = 0.010). There were no differences in gender, BMI, % body fat, visual acuity or contrast sensitivity between those with and without FMPD. % RBC membrane docosahexaenoic acid (DHA) was reduced in FMPD offspring vs. control offspring (P = 0.04). The Omega-3 Index was significantly decreased in the FMPD group (P = 0.03). CONCLUSIONS: The percentage of FMPD in AMD offspring is nearly twice that reported for the general population in the scientific literature. Offspring presenting FMPD had similar AMD genetic risk, but significantly reduced % RBC membrane omega-3 fatty acids and thinner foveas compared with those without FMPD. Our data supports the importance of 'essential fatty' acids as an independent AMD risk factor.

Efficacy and stability of a novel silica supplement for improving bone development in broilers.

1. The essentiality of silicon for skeletal development has been established, but the adequacy of bioavailable silicon supply in broiler diets has not been considered for 30 years, despite average daily weight gain of birds increasing by almost a third over that time. Therefore, two studies were undertaken to investigate whether modern strains of broiler chicken benefit from diet supplementation with bioavailable silica. 2. Trial 1 was a 2x2x2 factorial study where six replicate pens of seven chicks were fed one of the eight freshly prepared diets from hatch to 21 days of age, with bodyweight gain and feed intake recorded weekly. Diets combined the following factors: silicon supplement fed at 0 ppm or 1000 ppm, phytase levels of either 0 FTU/kg or 1500 FTU/kg and either 0.6% or 0.7% Ca. Tibia were analysed for bone breaking strength, extent of tibial dyschondroplasia and feet measured for bone ash and pododermatitis score. 3. Trial 2 used a 0.7% Ca with 1500 FTU phytase diet as the control and compared this with the same diet containing either 1000 ppm silicon (MONO-Si) freshly added each week or 1000 ppm silicon added in a single, advance-prepared batch per feeding phase. Each diet was fed to nine pens of seven birds from 0 to 35 d with feed consumption and weight recorded weekly. Two birds per pen were euthanised on d 14, 21 and 35 and tibias collected for measurement of bone breaking strength, ash and mineral content. Serum was collected for Si content. 4. Univariate analysis of means from each trial showed that silica supplementation improved bird weight gain over the starter phase, though there was no effect on feed conversion. 5. Bone strength improved with added silica in both studies, without affecting bone mineral content; indicating that modern strains of broiler may require dietary supplementation with bioavailable silicon.

Exogenous ATP in the Cryopreservation of Brycon orbignyanus Spermatozoa.

BACKGROUND: ATP exogenous (ATPe) has been used successfully in improving motility and fertility for many animal species. However this has not yet been tested on Brycon orbignyamus. OBJECTIVE: The objective of this study was to evaluate the use of ATPe for the cryopreservation of sperm from B. orbignyamus. MATERIALS AND METHODS: The ATPe concentrations tested were 1.0 µM, 5.0 µM and 10 µM combined with Beltsville Thawing SolutionTM extender and dimethylformamide at 7.5%. The sperm were frozen in a nitrogen vapour vessel and stored in liquid nitrogen at -196 ºC. The parameters of viability post-thawing were evaluated using CASA, and flow cytometer. RESULTS: The ATPe did not promote improvements in spermatic kinetics, and in the higher concentrations caused a worsening in these parameters. Also there was loss of mitochondrial functionality and greater cellular disruption with the concentration of 10 µM. CONCLUSION: We do not recommend the addition of ATP for cryopreserving B. orbignyamus.

Deep Uncertainties in Sea-Level Rise and Storm Surge Projections: Implications for Coastal Flood Risk Management.

Sea levels are rising in many areas around the world, posing risks to coastal communities and infrastructures. Strategies for managing these flood risks present decision challenges that require a combination of geophysical, economic, and infrastructure models. Previous studies have broken important new ground on the considerable tensions between the costs of upgrading infrastructure and the damages that could result from extreme flood events. However, many risk-based adaptation strategies remain silent on certain potentially important uncertainties, as well as the tradeoffs between competing objectives. Here, we implement and improve on a classic decision-analytical model (Van Dantzig 1956) to: (i) capture tradeoffs across conflicting stakeholder objectives, (ii) demonstrate the consequences of structural uncertainties in the sea-level rise and storm surge models, and (iii) identify the parametric uncertainties that most strongly influence each objective using global sensitivity analysis. We find that the flood adaptation model produces potentially myopic solutions when formulated using traditional mean-centric decision theory. Moving from a single-objective problem formulation to one with multiobjective tradeoffs dramatically expands the decision space, and highlights the need for compromise solutions to address stakeholder preferences. We find deep structural uncertainties that have large effects on the model outcome, with the storm surge parameters accounting for the greatest impacts. Global sensitivity analysis effectively identifies important parameter interactions that local methods overlook, and that could have critical implications for flood adaptation strategies.