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Abstract INTRODUCTION This ongoing, prospective study examines the effectiveness of methods used to successfully recruit and retain 238 Black older adults in a longitudinal, observational Alzheimer's disease (AD) study. METHODS Recruitment strategies included traditional media, established research registries, speaking engagements, community events, and snowball sampling. Participants were asked to complete an annual office testing session, blood‐based biomarker collection, optional one‐time magnetic resonance imaging (MRI) scan, and community workshop. RESULTS Within the first 22 months of active recruitment, 629 individuals expressed interest in participating, and 238 enrolled in the ongoing study. Of the recruitment methods used, snowball sampling, community events, and speaking engagements were the most effective. DISCUSSION The systemic underrepresentation of Black participants in AD research impacts the ability to generalize research findings and determine the effectiveness and safety of disease‐modifying treatments. Research to slow, stop, or prevent AD remains a top priority but requires diversity in sample representation. Highlights Provide flexible appointments in the evening or weekends, offering transportation assistance, and allowing participants to complete study visits at alternative locations, such as senior centers or community centers. Continuously monitor and analyze recruitment data to identify trends, challenges, and opportunities for improvement. Implement targeted strategies to recruit participants who are underrepresented based on sex, gender, or education to increase representation. Diversify the research team to include members who reflect the racial and cultural backgrounds of the target population, to enhance trust and rapport with prospective participants.

Abstract Information on fortifiable food consumption is essential to design, monitor and evaluate fortification programmes, yet detailed methods like 24‐h recalls (24HRs) that provide such data are rarely conducted. Simplified questionnaire‐based methods exist but their validity compared with 24HRs has not been shown. We compared two simplified methods (i.e., a household food acquisition and purchase questionnaire [FAPQ] and a 7‐day semiquantitative food frequency questionnaire [SQ‐FFQ]) against 24HRs for estimating fortifiable food consumption. We assessed the consumption of fortifiable wheat flour and oil using a FAPQ and, for wheat flour only, a 7‐day SQ‐FFQ and compared the results against 24HRs. The participants included children 12−18 months (n = 123) and their mothers 18−49 years selected for a study assessing child vitamin A intake and status in Mandaluyong City, Philippines. For fortifiable wheat flour, the FAPQ estimated considerably lower mean intakes compared to 24HRs for children and mothers (2.2 vs. 14.1 g/day and 5.1 vs. 42.3 g/day, respectively), while the SQ‐FFQ estimated slightly higher mean intakes (15.7 vs. 14.1 g/day and 51.5 vs. 42.3 g/day, respectively). For fortifiable oil, the FAPQ estimated considerably higher mean intakes compared to 24HRs for children and mothers (4.6 vs. 1.8 g/day and 12.5 vs. 6.1 g/day, respectively). The SQ‐FFQ, but not the FAPQ, generated useful information on fortifiable food consumption that can inform fortification programme design and monitoring decisions in the absence of more detailed individual‐level data. Potential adaptations to improve the FAPQ, such as additional questions on foods prepared away from home and usage patterns, merit further research.

Abstract Introduction This perspective paper addresses the US Hispanic/Latino (herein, Latino) experience with regards to a significant public health concern—the underrepresentation of Latino persons in Alzheimer's disease and related dementias (AD/ADRD) clinical trials. Latino individuals are at increased risk for AD/ADRD, experience higher disease burden, and low receipt of care and services. We present a novel theoretical framework—the Micro‐Meso‐Macro Framework for Diversifying AD/ADRD Trial Recruitment—which considers multi‐level barriers and their impact on Latino trial recruitment. Methods Based on a review of the peer‐reviewed literature and our lived experience with the Latino community, we drew from our interdisciplinary expertise in health equity and disparities research, Latino studies, social work, nursing, political economy, medicine, public health, and clinical AD/ADRD trials. We discuss factors likely to impede or accelerate Latino representation, and end with a call for action and recommendations for a bold path forward. Results In the 200+ clinical trials conducted with over 70,000 US Americans, Latino participants comprise a fraction of AD/ADRD trial samples. Efforts to recruit Latino participants typically address individual‐ and family‐level factors (micro‐level) such as language, cultural beliefs, knowledge of aging and memory loss, limited awareness of research, and logistical considerations. Scientific efforts to understand recruitment barriers largely remain at this level, resulting in diminished attention to upstream institutional‐ and policy‐level barriers, where decisions around scientific policies and funding allocations are ultimately made. These structural barriers are comprised of inadequacies or misalignments in trial budgets, study protocols, workforce competencies, healthcare‐related barriers, criteria for reviewing and approving clinical trial funding, criteria for disseminating findings, etiological focus and social determinants of health, among others. Conclusion Future scientific work should apply and test the Micro‐Meso‐Macro Framework for Diversifying AD/ADRD Trial Recruitment to examine structural recruitment barriers for historically underrepresented groups in AD/ADRD research and care.

Abstract Topics discussed at the “Leveraging Existing Data and Analytic Methods for Health Disparities Research Related to Aging and Alzheimer's Disease and Related Dementias” workshop, held by Duke University and the Alzheimer's Association with support from the National Institute on Aging, are summarized. Ways in which existing data resources paired with innovative applications of both novel and well‐known methodologies can be used to identify the effects of multi‐level societal, community, and individual determinants of race/ethnicity, sex, and geography‐related health disparities in Alzheimer's disease and related dementia are proposed. Current literature on the population analyses of these health disparities is summarized with a focus on identifying existing gaps in knowledge, and ways to mitigate these gaps using data/method combinations are discussed at the workshop. Substantive and methodological directions of future research capable of advancing health disparities research related to aging are formulated.

**Background:** Epidural analgesia can be associated with high costs and postsurgical risks such as hypotension, despite its widespread use and value in providing opioid-sparing pain management. We tested the hypothesis that liposomal bupivacaine (LB) might be a reliable alternative to epidural analgesia in this real-world study. **Objectives:** To compare economic outcomes and hypotension incidence associated with use of LB and epidural analgesia for abdominal surgery. **Methods:** This retrospective analysis identified records of adults who underwent abdominal surgeries between January 2016 and September 2019 with either LB administration or traditional epidural analgesia using the Premier Healthcare Database. Economic outcomes included length of stay, hospital costs, rates of discharge to home, and 30-day hospital readmissions. Secondary outcomes included incidence of postsurgical hypotension and vasopressor use. Subgroup analyses were stratified by surgical procedure (colorectal, abdominal) and approach (endoscopic, open). A generalized linear model adjusted for patient and hospital characteristics was used for all comparisons. **Results:** A total of 5799 surgical records (LB, n=4820; epidural analgesia, n=979) were included. Compared with cases where LB was administered, cases of epidural analgesia use were associated with a 1.6-day increase in length of stay (adjusted rate ratio [95% confidence interval (CI), 1.2 [1.2-1.3]]; _P_

Abstract The breakup of a slender filament of liquid driven by surface tension is a classical fluid dynamics stability problem that is important in many situations where fine droplets are required. When the filament is resting on a flat solid surface which imposes wetting conditions the subtle interplay with the fluid dynamics makes the instability pathways and mode selection difficult to predict. Here, we show how controlling the static and dynamic wetting of a surface can lead to repeatable switching between a toroidal film of an electrically insulating liquid and patterns of droplets of well-defined dimensions confined to a ring geometry. Mode selection between instability pathways to these different final states is achieved by dielectrophoresis forces selectively polarising the dipoles at the solid-liquid interface and so changing both the mobility of the contact line and the partial wetting of the topologically distinct liquid domains. Our results provide insights into the wetting and stability of shaped liquid filaments in simple and complex geometries relevant to applications ranging from printing to digital microfluidic devices.

Background The Delta and Omicron variants of SARS-CoV-2 are currently responsible for breakthrough infections due to waning immunity. We report phase I/II trial results of UB-612, a multitope subunit vaccine containing S1-RBD-sFc protein and rationally designed promiscuous peptides representing sarbecovirus conserved helper T cell and cytotoxic T lymphocyte epitopes on the nucleocapsid (N), membrane (M), and spike (S2) proteins.Method We conducted a phase I primary 2-dose (28 days apart) trial of 10, 30, or 100 μg UB-612 in 60 healthy young adults 20 to 55 years old, and 50 of them were boosted with 100 μg of UB-612 approximately 7 to 9 months after the second dose. A separate placebo-controlled and randomized phase II study was conducted with 2 doses of 100 μg of UB-612 (n = 3,875, 18–85 years old). We evaluated interim safety and immunogenicity of phase I until 14 days after the third (booster) dose and of phase II until 28 days after the second dose.Results No vaccine-related serious adverse events were recorded. The most common solicited adverse events were injection site pain and fatigue, mostly mild and transient. In both trials, UB-612 elicited respective neutralizing antibody titers similar to a panel of human convalescent sera. The most striking findings were long-lasting virus-neutralizing antibodies and broad T cell immunity against SARS-CoV-2 variants of concern (VoCs), including Delta and Omicron, and a strong booster-recalled memory immunity with high cross-reactive neutralizing titers against the Delta and Omicron VoCs.Conclusion UB-612 has presented a favorable safety profile, potent booster effect against VoCs, and long-lasting B and broad T cell immunity that warrants further development for both primary immunization and heterologous boosting of other COVID-19 vaccines.Trial Registration ClinicalTrials.gov: NCT04545749, NCT04773067, and NCT04967742.Funding UBI Asia, Vaxxinity Inc., and Taiwan Centers for Disease Control, Ministry of Health and Welfare.

The sea urchin embryo development toxicity test was used to investigate toxicity of the benthic substrate in Biscayne National Park (BISC). Twenty-five sites were selected based upon a high potential for anthropogenic stressor input (e. g., hydrocarbons, personal care products, nutrients, etc.) or proximity to coral reef habitats. We found that sediment interstitial water (porewater) was toxic to urchin embryos at 22 of 25 sites. Healthy sites included two coral reefs (Anniversary Reef and Marker 14 Reef) and Turkey Point Channel. Discrete areas of BISC have highly toxic sediments and the presence of sediment contaminants could negatively impact reproduction, growth and population density of benthic invertebrates, such as corals. Results of the sea urchin embryo development toxicity test can be used as a baseline assessment for monitoring improvements or degradation in ecosystem health and could be a valuable tool to investigate the suitability of degraded habitats for future reef restoration. Since the last comprehensive environmental assessment of BISC was performed in 1999, further investigation into the sources of toxicity at BISC is needed.

Abstract Background The range of risk reduced alternatives to smoking tobacco is increasing and so is use among pregnant women. The substantial harms of smoking during pregnancy are well established and there is reason to believe that nicotine alone is somewhat harmful. Differences in the exposure chemistry strongly suggest that the effects of using smoke-free nicotine products (including pharmaceutical nicotine products, smokeless tobacco, and electronic cigarettes containing nicotine) fall somewhere in the range between zero risk to the risk from smoking. How much lower risk these consumption choices are in terms of pregnancy outcomes, however, remains uncertain. Methods We reviewed the literature on smoke-free nicotine and tobacco product exposure and birth-outcome endpoints. Studies were included if they compared outcomes to either no nicotine use or smoking. We searched Google Scholar using broad search terms and additional articles were snowballed from citations. We report what could be learned from each study, given its methods. Results Of the 21 studies reviewed, 12 reported on the use of nicotine replacement therapies, 7 on Swedish snus, 1 on Alaskan iq’mik, and 1 on e-cigarettes. The range of results tends to support the prediction that smoke-free product use during pregnancy probably increases the risk of some negative birth outcomes, but that any effect is less than that from smoking. However, the limitations of epidemiology are such that no more-precise a conclusion is possible. Discussion The available epidemiology does not change our prior beliefs, based on other evidence and knowledge, that the risks from smoke-free nicotine and tobacco are lower than those for smoking, though it suggests they are non-zero. However, it also demonstrates that the epidemiology is unlikely to provide precise quantitative estimates. This is not just a matter of lack of studies; given the inherent limitation of these studies, doubling or tripling the corpus of available studies would add little precision. For the foreseeable future, decisions about using these products will need to be made based on rough estimates, based on a variety of forms of evidence, and qualitative comparisons.

Health disparities are defined on the basis of specific populations that, when compared to the general population, have a significant disparity on the rate of disease incidence, prevalence, morbidity, mortality, or survival. People that experience health disparities can be defined by multiple criteria. As the diversity of the United States broadens and increases, research on the origins and causes of health disparities becomes more important to support a healthy general population. Children are particularly sensitive to and vulnerable to health disparities due to the potentially life long consequences of events during periods of critical organ, intellectual and social development. The concept of health justice whereby each individual has the opportunity to realize their full health potential can only be realized with proper understanding and relevant data to frame practice, policy and actions. The National Children's Study (NCS) was a longitudinal birth cohort study designed to incorporate the principles of the Federal Collaboration on Health Disparities Research in consultation with subject matter experts, community representatives, and ongoing evaluation to ensure high quality and relevant data on factors that impact health outcomes. The NCS developed and tested a model of enrolling a diverse population, capturing and integrating data using a life course framework, constructing individual profiles, then aggregating individuals into groups based on profiles and outcomes. This approach is applicable to other longitudinal cohort studies.

Background and study aim COVID-19 patients are at increased risk for venous thromboembolism (VTE) requiring the use of anticoagulation. Gastrointestinal bleeding (GIB) is increasingly being reported, complicating the decision to initiate or resume anticoagulation as providers balance the risk of thrombotic disease with the risk of bleeding. Our study aimed to assess rebleeding rates in COVID-19 patients with GIB and determine whether endoscopy reduces these rebleeding events. We also report 30-day VTE and mortality rates. Methods This was a retrospective study evaluating 56 COVID-19 patients with GIB for the following outcomes: 30-day rebleeding rate, 30-day VTE rate, effects of endoscopic intervention on the rate of rebleeding, and 30-day mortality. Results The overall rates of VTE and rebleeding events were 27 % and 41 %, respectively. Rebleeding rates in patients managed conservatively was 42 % compared with 40 % in the endoscopy group. Overall, 87 % of those who underwent invasive intervention resumed anticoagulation vs. 55 % of those managed medically (P = 0.02). The all-cause 30-day mortality and GIB-related deaths were 32 % and 9 %, respectively. Mortality rates between the endoscopic and conservative management groups were not statistically different (25 % vs. 39 %; P = 0.30). Conclusions Although rebleeding rates were similar between the endoscopic and conservative management groups, patients who underwent intervention were more likely to restart anticoagulation. While endoscopy appeared to limit the duration that anticoagulation was withheld, larger studies are needed to further characterize its direct effect on mortality outcomes in these complex patients.

Background and study aims Acute pancreatitis (AP) is an increasingly common indication for hospitalization in the United States. The necessity for endoscopic retrograde cholangiopancreatography (ERCP) and the timing of ERCP in acute gallstone-related pancreatitis without cholangitis (AGPNC) is controversial. The aim of this study was to evaluate the association of ERCP and its performance during admission with mortality and length of stay (LOS) in patients with AGPNC. Patients and methods We queried the Nationwide Inpatient Sample (NIS) from 2004 to 2014 to identify all patients with admissions for gallstone AP. We excluded patients with chronic pancreatitis or concurrent cholangitis, and those who were transferred from elsewhere for treatment. Our primary outcome measure was inpatient mortality. Our secondary outcome measure was hospital length of stay (LOS). Results We identified 491,011 records eligible for analysis. Of the patients, 30.6 % (150,101) had AGPNC. There were 1.34 deaths per 100 admissions in patients with AGPNC. The average LOS was 5.88 (± 6.38) days with a median stay of 4 days (range, 3–7). When adjusted for age, Elixhauser Comorbidity Index, and severe pancreatitis, patients with ERCP during admission were 43 % less likely to die. ERCP performed between Days 3 and 9 of hospitalization resulted in a significant mortality benefit. Among those who had ERCP, a shorter wait time for ERCP was associated with a shorter LOS after adjustment for demographics and severity of illness. Conclusion ERCP performed during inpatient admission for AGPNC was associated with decreased mortality. These data support early ERCP in patients with acute gallstone pancreatitis without cholangitis.

BackgroundGiven the challenges and costs associated with implementing HIV-1 incidence assay testing, there is great interest in evaluating the use of commercial HIV diagnostic tests for determining recent HIV infection. A diagnostic test with the capability of providing reliable data for the determination of recent HIV infection without substantial modifications to the test protocol would have a significant impact on HIV surveillance. The Abbott ARCHITECT HIV Ag/Ab Combo Assay is an antigen/antibody immunoassay, which meets the criteria as the first screening test in the recommended HIV laboratory diagnostic algorithm for the United States.MethodsIn this study, we evaluated the performance characteristics of the ARCHITECT HIV Ag/Ab Combo signal-to-cutoff ratio (S/Co) for determining recent infection, including estimation of the mean duration of recent infection (MDRI) and false recent rate (FRR), and selection of recency cutoffs.ResultsThe MDRI estimates for the S/Co recency cutoff of 400 is within the 4 to 12 months range recommended for HIV incidence assays, and the FRR rate for this cutoff was 1.5%. Additionally, ARCHITECT Combo S/Co values were compared relative to diagnostic test results from two prior prospective HIV-1 diagnostic studies in order to validate the use of the S/Co for both diagnostic and recency determination.ConclusionDual-use of the ARCHITECT Combo assay data for diagnostic and incidence purposes would reduce the need for separate HIV incidence testing and allow for monitoring of recent infection for incidence estimation and other public health applications.

Aging in the United States will be defined by differences in health and longevity among populations. Diversity among the aged population is expected to increase. While investigators must contend with generalizability to enhance rigor, biomedical research holds great promise in exploring determinants of health for populations groups. Biomedical research explores the impact of various determinants on health and longevity. Health disparities research related to aging serves as an important scientific approach for researchers to maintain clarity in generalizability, with a focus on a breadth of determinants in multiple levels of analysis. Moreover, health disparities research related to aging holds the biomedical research enterprise accountable to principles of equity for understanding and addresing the health and aging of disproportionately affected population groups in society.

Youth gambling is an increasing concern. As a response, the "Don't Gamble Away our Future (DGAOF)" program has been implemented among children in central Illinois. We aim to assess the long-term effectiveness of this school-based youth gambling prevention program in Illinois using the data from 2005 to 2009. The intervention included interactive PowerPoint presentations and prevention materials in parent packets. Students aged 8 to 18 years were eligible to participate in the intervention and the questionnaire pre-post knowledge tests (total score 0-9). Students in 5th grade and above also received a gambling behavior screen test using the Modified South Oaks Gambling Screening for Teens (MSOGST) for identifying probable gamblers. Multivariable generalized mixed models were conducted to detect the effects of a 5-year youth gambling prevention program as controlling potential confounders. A total of 16,262 and 16,421 students completed pre-post tests and MSOGST tests, respectively. Of 16,262, half were female, the majority (76.1%) were from senior high school, and 21.3% received the intervention at least twice. The median gap between interventions was 368 days. Students receiving multiple interventions had higher scores on the pre-test as compared to those receiving a single intervention (P

BackgroundThis study aims to assess the decline in telomere length (TL) with age and evaluate effect modification by gender, chronic stress, and comorbidity in a representative sample of the US population.MethodsCross-sectional data on 7826 adults with a TL measurement, were included from the National Health and Nutrition Examination Survey, years 1999-2002. The population rate of decline in TL across 10-year age categories was estimated using crude and adjusted regression.ResultsIn an adjusted model, the population rate of decline in TL with age was consistent and linear for only three age categories: 20-29 (β = -0.0172, 95% CI: -0.0342, -0.0002), 50-59 (β = -0.0182, 95% CI: -0.0311, -0.0054) and 70-79 (β = -0.0170, 95% CI: -0.0329, -0.0011) years. The population rate of decline in TL with age was significantly greater for males and those with high allostatic load and a history of comorbidities. When the population rate of decline in TL was analyzed by gender in 10-year age bins, a fairly consistent yet statistically non-significant decline for males was observed; however, a trough in the rate was observed for females in the age categories 20-29 years (β = -0.0284, 95% CI: -0.0464, -0.0103) and 50-59 years (β = -0.0211, 95% CI: -0.0391, -0.0032). To further elucidate the gender difference observed in the primary analyses, secondary analyses were conducted with reproductive and hormonal status; a significant inverse association was found between TL and parity, menopause, and age at menopause.ConclusionsTL was shorter with increasing age and this decline was modified by gender, chronic stress and comorbidities; individuals with chronic morbidity and/or chronic stress and females in their twenties and fifties experienced greater decline. Female reproductive factors, i.e., parity and menopause, were associated with TL.

Background: High-quality bowel preparation is crucial for achieving the goals of colonoscopy. However, choosing a bowel preparation in clinical practice can be challenging because of the many formulations. This study aims to assess the impact the type of bowel preparation on the quality of colonoscopy in a community hospital setting. Methods: A retrospective, observational study was conducted utilizing a colonoscopy screening/surveillance database in central Illinois during the period of January 1, 2010, to March 31, 2014. Patients without bowel preparation assessment were excluded from this study. Controlling for the confounders, generalized linear models were used to estimate the adjusted impact [odds ratio (OR)] of bowel preparation type on the quality of preparation (excellent, good, fair, and poor), and on the detection of advanced adenoma. The association between the time of withdrawal after insertion and the quality of preparation was also examined using a linear model. Results: A total of 28,368 colonoscopies; half the patients were male, and the average age was 61±9 years. Polyethylene glycol (PEG) was used in the majority (70.2%) of bowel preparations, followed by sodium sulfate (21.4%), sodium phosphate (2.5%), magnesium sulfate (0.4%), and others. Compared with PEG, magnesium sulfate had a poorer quality of bowel preparations (OR=0.6, 95% CI 0.4–0.9; p

Breast cancer is the most common cancer type and a primary cause of cancer mortality among females worldwide. Here, we analyzed the anticancer efficacy of a novel bromochlorinated monoterpene, PPM1, a synthetic analogue of polyhalogenated monoterpenes from Plocamium red algae and structurally similar non-brominated monoterpenes. PPM1, but not the non-brominated monoterpenes, decreased selectively the viability of several triple-negative as well as triple-positive breast cancer cells with different p53 status without significantly affecting normal breast epithelial cells. PPM1 induced accumulation of triple-negative MDA-MB-231 cells with 4N DNA content characterized by decreased histone H3-S10/T3 phosphorylation indicating cell cycle arrest in the G2 phase. Western immunoblot analysis revealed that PPM1 treatment triggered an initial rapid activation of Aurora kinases A/B/C and p21Waf1/Cip1 accumulation, which was followed by accumulation of polyploid >4N cells. Flow cytometric analysis showed mitochondrial potential disruption, caspase 3/7 activation, phosphatidylserine externalization, reduction of the amount polyploid cells, and DNA fragmentation consistent with induction of apoptosis. Cell viability was partially restored by the pan-caspase inhibitor Z-VAD-FMK indicating caspase contribution. In vivo, PPM1 inhibited growth, proliferation, and induced apoptosis in MDA-MB-231 xenografted onto the chick chorioallantoic membrane. Hence, Plocamium polyhalogenated monoterpenes and synthetic analogues deserve further exploration as promising anticancer lead compounds.

SLT-VEGF is a recombinant cytotoxin comprised of Shiga-like toxin (SLT) subunit A fused to human vascular endothelial growth factor (VEGF). It is highly cytotoxic to tumor endothelial cells overexpressing VEGF receptor-2 (VEGFR-2/KDR/Flk1) and inhibits the growth of primary tumors in subcutaneous models of breast and prostate cancer and inhibits metastatic dissemination in orthotopic models of pancreatic cancer. We examined the efficacy of SLT-VEGF in limiting tumor growth and metastasis in an orthotopic melanoma model, using NCR athymic nude mice inoculated with highly metastatic Line IV Cl 1 cultured human melanoma cells. Twice weekly injections of SLT-VEGF were started when tumors became palpable at one week after intradermal injection of 1 × 106 cells/mouse. Despite selective depletion of VEGFR-2 overexpressing endothelial cells from the tumor vasculature, SLT-VEGF treatment did not affect tumor growth. However, after primary tumors were removed, continued SLT-VEGF treatment led to fewer tumor recurrences (p = 0.007), reduced the incidence of lung metastasis (p = 0.038), and improved survival (p = 0.002). These results suggest that SLT-VEGF is effective at the very early stages of tumor development, when selective killing of VEGFR-2 overexpressing endothelial cells can still prevent further progression. We hypothesize that SLT-VEGF could be a promising adjuvant therapy to inhibit or prevent outgrowth of metastatic foci after excision of aggressive primary melanoma lesions.

Diverse physiological and therapeutic insults that increase the amount of unfolded or misfolded proteins in the endoplasmic reticulum (ER) induce the unfolded protein response, an evolutionarily conserved protective mechanism that manages ER stress. Glucose-regulated protein 78/immunoglobulin heavy-chain binding protein (GRP78/BiP) is an ER-resident protein that plays a central role in the ER stress response and is the only known substrate of the proteolytic A subunit (SubA) of a novel bacterial AB5 toxin. Here, we report that an engineered fusion protein, epidermal growth factor (EGF)-SubA, combining EGF and SubA, is highly toxic to growing and confluent epidermal growth factor receptor-expressing cancer cells, and its cytotoxicity is mediated by a remarkably rapid cleavage of GRP78/BiP. Systemic delivery of EGF-SubA results in a significant inhibition of human breast and prostate tumor xenografts in mouse models. Furthermore, EGF-SubA dramatically increases the sensitivity of cancer cells to the ER stress-inducing drug thapsigargin, and vice versa, demonstrating the first example of mechanism-based synergism in the action of a cytotoxin and an ER-targeting drug.

We previously identified several peptide sequences that mimicked the terminal sugars of complex glycans. Using plant lectins as analogs of lectin-type cell-surface receptors, a tetravalent form of a peptide with the sequence NPSHPLSG, designated svH1C, bound with high avidity to lectins specific for glycans with terminal 5-acetylneuraminic acid (Neu5Ac)-galactose (Gal)/N-acetylgalactosamine (GalNAc) sequences. In this report, we show by circular dichroism and NMR spectra that svH1C lacks an ordered structure and thus interacts with binding sites from a flexible conformation. The peptide binds with high avidity to several recombinant human siglec receptors that bind preferentially to Neu5Ac(α2,3)Gal, Neu5Ac(α2,6)GalNAc or Neu5Ac(α2,8)Neu5Ac ligands. In addition, the peptide bound the receptor NKG2D, which contains a lectin-like domain that binds Neu5Ac(α2,3)Gal. The peptide bound to these receptors with a KD in the range of 0.6 to 1 μM. Binding to these receptors was inhibited by the glycoprotein fetuin, which contains multiple glycans that terminate in Neu5Ac(α2,3)Gal or Neu5Ac(α2,6)Gal, and by sialyllactose. Binding of svH1C was not detected with CLEC9a, CLEC10a or DC-SIGN, which are lectin-type receptors specific for other sugars. Incubation of neuraminidase-treated human peripheral blood mononuclear cells with svH1C resulted in binding of the peptide to a subset of the CD14+ monocyte population. Tyrosine phosphorylation of siglecs decreased dramatically when peripheral blood mononuclear cells were treated with 100 nM svH1C. Subcutaneous, alternate-day injections of svH1C into mice induced several-fold increases in populations of several types of immune cells in the peritoneal cavity. These results support the conclusion that svH1C mimics Neu5Ac-containing sequences and interacts with cell-surface receptors with avidities sufficient to induce biological responses at low concentrations. The attenuation of inhibitory receptors suggests that svH1C has characteristics of a checkpoint inhibitor.

Patients with metastatic or recurrent and refractory sarcomas have a dismal prognosis. Therefore, new targeted therapies are urgently needed. This study was designed to evaluate chimeric antigen receptor (CAR) T cells targeting the type I insulin-like growth factor receptor (IGF1R) or tyrosine kinase-like orphan receptor 1 (ROR1) molecules for their therapeutic potential against sarcomas. Here, we report that IGF1R (15/15) and ROR1 (11/15) were highly expressed in sarcoma cell lines including Ewing sarcoma, osteosarcoma, alveolar or embryonal rhabdomyosarcoma, and fibrosarcoma. IGF1R and ROR1 CAR T cells derived from eight healthy donors using the Sleeping Beauty (SB) transposon system were cytotoxic against sarcoma cells and produced high levels of IFN-γ, TNF-α and IL-13 in an antigen-specific manner. IGF1R and ROR1 CAR T cells generated from three sarcoma patients released significant amounts of IFN-γ in response to sarcoma stimulation. The adoptive transfer of IGF1R and ROR1 CAR T cells derived from a sarcoma patient significantly reduced tumor growth in pre-established, systemically disseminated and localized osteosarcoma xenograft models in NSG mice. Infusion of IGF1R and ROR1 CAR T cells also prolonged animal survival in a localized sarcoma model using NOD/scid mice. Our data indicate that both IGF1R and ROR1 can be effectively targeted by SB modified CAR T cells and that such CAR T cells may be useful in the treatment of high risk sarcoma patients.

The purpose of this study was to determine independent influences of functional level and lower limb amputation type on inpatient rehabilitation outcomes. We conducted a secondary data analysis for patients with lower limb amputation who received inpatient medical rehabilitation (N = 26,501). The study outcomes included length of stay, discharge functional status, and community discharge. Predictors included the 3-level case mix group variable and a 4-category amputation variable. Age of the sample was 64.5 years (13.4) and 64% were male. More than 75% of patients had a dysvascular-related amputation. Patients with bilateral transfemoral amputations and higher functional severity experienced longest lengths of stay (average 13.7 days) and lowest functional rating at discharge (average 79.4). Likelihood of community discharge was significantly lower for those in more functionally severe patients but did not differ between amputation categories. Functional levels and amputation type are associated with rehabilitation outcomes in inpatient rehabilitation settings. Patients with transfemoral amputations and those in case mix group 1003 (admission motor score less than 36.25) generally experience poorer outcomes than those in other case mix groups. These relationships may be associated with other demographic and/or health factors, which should be explored in future research.

The Alzheimer's Association hosted the second Latinos & Alzheimer's Symposium in May 2021. Due to the COVID-19 pandemic, the meeting was held online over 2 days, with virtual presentations, discussions, mentoring sessions, and posters. The Latino population in the United States is projected to have the steepest increase in Alzheimer's disease (AD) in the next 40 years, compared to other ethnic groups. Latinos have increased risk for AD and other dementias, limited access to quality care, and are severely underrepresented in AD and dementia research and clinical trials. The symposium highlighted developments in AD research with Latino populations, including advances in AD biomarkers, and novel cognitive assessments for Spanish-speaking populations, as well as the need to effectively recruit and retain Latinos in clinical research, and how best to deliver health-care services and to aid caregivers of Latinos living with AD.

Background and aimsKidney dysfunction is associated with increased mortality among patients with cirrhosis. We investigated whether kidney dysfunction types [e.g., acute kidney injury (AKI), chronic kidney disease (CKD), and AKI on CKD] were differentially associated with inpatient mortality.MethodsWe utilized the nationwide inpatient sample, a nationally representative database, from 2007 to 2014. We included all hospitalizations with previously validated codes for cirrhosis or associated decompensated cirrhosis diagnoses. We defined kidney dysfunction types also from previously validated codes, and we grouped hospitalizations into the following diagnoses: normal, AKI, CKD, and AKI on CKD. Our primary outcome was inpatient mortality.ResultsThere were 1,293,779 hospitalizations with cirrhosis sampled in this study. Of these hospitalizations, 849,193 (66%) had normal kidney function, 176,418 (14%) had AKI, 157,600 (12%) had CKD, and 110,568 (9%) had AKI on CKD. We found that the proportion of hospitalizations with AKI, CKD, and AKI on CKD increased significantly throughout the study period (p

The immunodominant epitopes expressed by the HIV-1 envelope protein gp120 are hypermutable, defeating attempts to develop an effective HIV vaccine. Targeting the structurally conserved gp120 determinant that binds host CD4 receptors (CD4BD) and initiates infection is a more promising route to vaccination, but this has proved difficult because of the conformational flexibility of gp120 and immune evasion mechanisms used by the virus. Mimicking the outer CD4BD conformational epitopes is difficult because of their discontinuous nature. The CD4BD region composed of residues 421-433 (CD4BDcore) is a linear epitope, but this region possesses B cell superantigenic character. While superantigen epitopes are vulnerable to a small subset of spontaneously-produced neutralizing antibodies present in humans without infection (innate antibodies), their noncovalent binding to B cell receptors (BCRs) does not stimulate an effective adaptive response from B cells. Covalent binding at naturally-occurring nucleophilic sites of the BCRs by an electrophilic gp120 analog (E-gp120) is a promising solution. E-gp120 induces the synthesis of neutralizing antibodies the CD4BDcore. The highly energetic covalent reaction is hypothesized to convert the abortive superantigens-BCR interaction into a stimulatory signal, and the binding of a spatially distinct epitope at the traditional combining site of the BCRs may furnish a second stimulatory signal. Flexible synthetic peptides can detect pre-existing CD4BDcore-specific neutralizing antibodies. However, induced-fit conformational transitions of the peptides dictated by the antibody combining site structure may induce the synthesis of non-neutralizing antibodies. Successful vaccine targeting of the CD4BD will require a sufficiently rigid immunogen that mimic the native epitope conformation and bypasses B cell checkpoints restricting synthesis of the neutralizing antibodies.

The development of a topical microbicide blocking the sexual transmission of HIV-1 is urgently needed to control the global HIV/AIDS pandemic. The actinomycete-derived lectin actinohivin (AH) is highly specific to a cluster of high-mannose-type glycans uniquely found on the viral envelope (Env). Here, we evaluated AH's candidacy toward a microbicide in terms of in vitro anti-HIV-1 activity, potential side effects, and recombinant producibility. Two validated assay systems based on human peripheral blood mononuclear cell (hPBMC) infection with primary isolates and TZM-bl cell infection with Env-pseudotyped viruses were employed to characterize AH's anti-HIV-1 activity. In hPMBCs, AH exhibited nanomolar neutralizing activity against primary viruses with diverse cellular tropisms, but did not cause mitogenicity or cytotoxicity that are often associated with other anti-HIV lectins. In the TZM-bl-based assay, AH showed broad anti-HIV-1 activity against clinically-relevant, mucosally transmitting strains of clades B and C. By contrast, clade A viruses showed strong resistance to AH. Correlation analysis suggested that HIV-1's AH susceptibility is significantly linked to the N-glycans at the Env C2 and V4 regions. For recombinant (r)AH expression, we evaluated a tobacco mosaic virus-based system in Nicotiana benthamiana plants as a means to facilitate molecular engineering and cost-effective mass production. Biochemical analysis and an Env-mediated syncytium formation assay demonstrated high-level expression of functional rAH within six days. Taken together, our study revealed AH's cross-clade anti-HIV-1 activity, apparent lack of side effects common to lectins, and robust producibility using plant biotechnology. These findings justify further efforts to develop rAH toward a candidate HIV-1 microbicide.

Abstract: Black/African Americans represent 13% of the population, yet account for more than 24% of COVID-19 deaths. Emerging evidence indicates that Black Americans are receiving COVID-19 vaccines at lower rates than whites. However, there is minimal information about why vaccination rates are lower. To address this gap, we examined the effects of the COVID-19 pandemic among Black Americans, with an emphasis on understanding trust and vaccine uptake. Data were collected between July and September 2020 using 8 virtual focus groups in Detroit, MI and San Francisco Bay Area, CA with 33 older Black Americans and 11 caregivers of older Black Americans with cognitive impairment. Inductive/deductive content analysis was used to identify themes. The first theme pointed to a sense of feeling abandoned by healthcare providers and the government at local and state levels, which exacerbated uncertainty and fear about the vaccine and in general. The second theme emphasized a sense of deep distrust towards healthcare providers and the government, especially during the pandemic. The third theme pointed to a reluctance in receiving the vaccine because of distrust of pharmaceutical companies and the government, as well as misinformation and the rapid speed of vaccine development. These findings suggest that underlying systemic issues need to be addressed immediately to accelerate vaccine uptake among older Black Americans. New initiatives are needed to foster trust and address abandonment by healthcare and government systems. In addition, public health campaigns with reliable information about the COVID-19 vaccine are needed.

Background & aimsFecal microbiota transplantation (FMT) is used commonly for treatment of Clostridioides difficile infections (CDIs), although prospective safety data are limited and real-world FMT practice and outcomes are not well described. The FMT National Registry was designed to assess FMT methods and both safety and effectiveness outcomes from North American FMT providers.MethodsPatients undergoing FMT in clinical practices across North America were eligible. Participating investigators enter de-identified data into an online platform, including FMT protocol, baseline patient characteristics, CDI cure and recurrence, and short and long-term safety outcomes.ResultsOf the first 259 participants enrolled at 20 sites, 222 had completed short-term follow-up at 1 month and 123 had follow-up to 6 months; 171 (66%) were female. All FMTs were done for CDI and 249 (96%) used an unknown donor (eg, stool bank). One-month cure occurred in 200 patients (90%); of these, 197 (98%) received only 1 FMT. Among 112 patients with initial cure who were followed to 6 months, 4 (4%) had CDI recurrence. Severe symptoms reported within 1-month of FMT included diarrhea (n = 5 [2%]) and abdominal pain (n = 4 [2%]); 3 patients (1%) had hospitalizations possibly related to FMT. At 6 months, new diagnoses of irritable bowel syndrome were made in 2 patients (1%) and inflammatory bowel disease in 2 patients (1%).ConclusionsThis prospective real-world study demonstrated high effectiveness of FMT for CDI with a good safety profile. Assessment of new conditions at long-term follow-up is planned as this registry grows and will be important for determining the full safety profile of FMT.

Black/African American populations are underrepresented as participants in dementia research. A major barrier to participation of African American older adults in dementia research is a tendency to distrust research institutions owing to both historical and contemporary racism. Building on the Ford framework, the objective of our study was to examine factors that influence participation in dementia research among African American older adults and caregivers, with an emphasis on understanding factors related to trust. Data were collected during January 2019 and March 2020 from 10 focus groups with African American older adults (n=91), 5 focus groups with caregivers (n=44), and interviews with administrators of community-based organizations (n=11), and meetings with our Community Advisory Board. Inductive/deductive content analysis was used to identify themes. The results identified an overall tension between distrust of researchers and a compelling desire to engage in dementia research. This overarching theme was supported by six themes that provided insights about the multiple layers of distrust, as well as expectations about the appropriate conduct of researchers and academic institutions. Strong commitment to the community was identified as a priority. The findings suggest that a paradigm shift is needed to increase the representation of African Americans in dementia research. In this new paradigm, earning the trust of African American communities becomes a systemic endeavor, with academic, state, and national institutions deeply committed to earning the trust of African American communities and guiding researchers in this endeavor. The findings also generated actionable recommendations to help improve representation of African American older adults in dementia research.

Health systems often fail to tap the expertise of the developmental disabilities community support and service system. In this 9-month pilot health system-level quality improvement project, a multi-disciplinary team of physician, pharmacist, and disabilities advocate reviewed electronic records of patients with Down syndrome in advance of pre-scheduled appointments with their primary care physician (PCP) and generated 100 electronic consultations. Post-consultation chart review documented meaningful uptake of clinical recommendations, including screening for thyroid disease, celiac disease, and heart disease, pneumococcal vaccination, and screening physical examination for myelopathy. In addition to clinical recommendations regarding screening, diagnosis, and treatment, each consultation provided an average of eight tailored suggestions for potential community-based resources related to mental and behavioral health, recreation, socialization, and other relevant services and supports. "Push" multi-disciplinary electronic consultations in advance of primary care appointments enriched with input from disabilities community experts have the potential to improve the quality of health care provided to persons with developmental disabilities.

Breast cancer is the most common cancer type and a primary cause of cancer mortality among females worldwide. Here, we analyzed the anticancer efficacy of a novel bromochlorinated monoterpene, PPM1, a synthetic analogue of polyhalogenated monoterpenes from Plocamium red algae and structurally similar non-brominated monoterpenes. PPM1, but not the non-brominated monoterpenes, decreased selectively the viability of several triple-negative as well as triple-positive breast cancer cells with different p53 status without significantly affecting normal breast epithelial cells. PPM1 induced accumulation of triple-negative MDA-MB-231 cells with 4N DNA content characterized by decreased histone H3-S10/T3 phosphorylation indicating cell cycle arrest in the G2 phase. Western immunoblot analysis revealed that PPM1 treatment triggered an initial rapid activation of Aurora kinases A/B/C and p21Waf1/Cip1 accumulation, which was followed by accumulation of polyploid >4N cells. Flow cytometric analysis showed mitochondrial potential disruption, caspase 3/7 activation, phosphatidylserine externalization, reduction of the amount polyploid cells, and DNA fragmentation consistent with induction of apoptosis. Cell viability was partially restored by the pan-caspase inhibitor Z-VAD-FMK indicating caspase contribution. In vivo, PPM1 inhibited growth, proliferation, and induced apoptosis in MDA-MB-231 xenografted onto the chick chorioallantoic membrane. Hence, Plocamium polyhalogenated monoterpenes and synthetic analogues deserve further exploration as promising anticancer lead compounds.

Background Antibiotic use is a major risk factor for recurrent Clostridioides difficile infection (CDI) due to the associated disruption in gut microbiota. Fecal microbiota, live-jslm (REBYOTA®; RBL, previously RBX2660), is the first microbiota-based live biotherapeutic approved by the US Food and Drug Administration to prevent recurrent CDI in adults following standard-of-care antibiotic treatment. To investigate the impact of non-CDI antibiotics on the durability of RBL, a subgroup analysis was conducted on PUNCH™ Open-Label study participants who received non-CDI antibiotics during the period between RBL administration and up to 2 years after. Methods Participants in PUNCH™ Open-Label who received non-CDI antibiotics after RBL administration were included in this subgroup analysis. Treatment response was defined as the absence of CDI diarrhea needing retreatment at the last evaluable time point (8 weeks, 6 months, 1 year, or 2 years) after RBL administration. Results Among participants from PUNCH™ Open-Label, 43 received non-CDI antibiotics after RBL administration but before CDI recurrence as evaluated over a 2-year period. Across all evaluable time points, 86% (37/43) of participants had a treatment response regardless of when non-CDI antibiotic exposure occurred. Treatment response was sustained for a median 470 days (IQR, 212–648) from the first day of non-CDI antibiotic use. Most participants (5/6) with CDI recurrences received a high-risk antibiotic. Conclusions RBL remained efficacious in participants with a history of recurrent CDI after subsequent non-CDI antibiotic exposure. Clinical Trials Registration NCT02589847 (https://clinicaltrials.gov/study/NCT02589847). [ABSTRACT FROM AUTHOR]

Why did our idea not work out? How did a program fail? Why did we get unintended consequences? Who is to blame? Could it be that our best just isn't good enough? There are many reasons policies, programs and projects fail. Failure can be informative if shared. This means that professionals should report on failures as well as successes. However, few professionals will admit their mistakes since failures are seldom rewarded. Moreover, many failures that could provide useful guidance are not shared because most journals have a success bias. Oftentimes, however, a policy failure where "NO" was the answer can provide useful information. In this article the author urges readers to accept that humans fail, but if professionals are to learn from failure, improve skills, and manage strategic change, it is necessary to understand why policies and programs fail. As difficult as it is, professionals need to have the courage to speak truth to power when things are not going right. Author Carl Patton argues that if there were easier access to internationalization ideas that failed, other educators could more rapidly improve their professional competence. Patton closes the article by saying that failure is inevitable, but the question is how will colleagues respond to one another, support one another, and move forward.