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Fabrication of Ti3SiC2 from elemental powder compacts was conducted by combustion synthesis in the mode of self-propagating high-temperature synthesis (SHS). Samples were formulated with three atomic ratios of Ti:Si:C = 3:1:2, Ti:Si:C = 3:1.2:2 (with excess Si by 20 mol.%), and Ti:Si:C:Al = 3:1.2:2:0.1 (a Si-rich and Al-added composition). Combustion reaction was highly exothermic and combustion wave velocity (from 4.1 to 8.8 mm/s) and temperature (from 1340 to 1610 °C) increased significantly with sample compact density varied in the range of 45% to 57.5% TMD (theoretical maximum density). In addition to the sample density, excess Si and a small amount of Al contributed greatly to the formation of Ti3SiC2. For the powder compacts of 57.5% TMD, the product synthesized from the sample of Ti:Si:C = 3:1:2 was composed of Ti3SiC2, TiC, and Ti5Si3 at 64 wt.%, 28 wt.%, and 8 wt.%, respectively. The sample with excess Si by 20 mol.% yielded a product with a weight proportion of Ti3SiC2:TiC:Ti5Si3 = 70:27:3. The product having the highest yield of Ti3SiC2 was obtained from the Si-rich/Al-added sample, which produced Ti3SiC of 83 wt.%, TiC of 13 wt.% and Ti5Si3 of 4 wt.%. As-synthesized Ti3SiC2 grains were in a thin plate-like shape with 0.5–1.5 µm in thickness and 5–10 µm in length. Ti3SiC2 platelets were stacked closely into a layered structure. [ABSTRACT FROM AUTHOR]

The aim of this study was to develop a model for predicting the risk of postoperative temporomandibular joint osteoarthritis (TMJOA) in patients receiving a segmental or marginal mandibulectomy for oral cavity cancer . A total of 371 patients with buccal or gingival cancer who underwent mandibulectomy were included in this retrospective cohort study. Demographic data, computed tomography, and magnetic resonance images were reviewed. Univariate and multivariate Cox regression analyses were performed to develop a nomogram to predict post-mandibulectomy TMJOA. TMJOA was identified in 81 of the 371 patients at 2 years and 107 at 4 years. The predictors of post-mandibulectomy TMJOA were segmental mandibulectomy (hazard ratio (HR) 2.51, 95% confidence interval (CI) 1.64-3.83, P < 0.001), age ≥ 62.5 years (HR 2.28, 95% CI 1.53-3.40, P < 0.001), BMI < 24.1 kg/m 2 (HR 2.13, 95% CI 1.45-3.13, P < 0.001), and American Joint Committee on Cancer stage IVa/IVb (HR 2.21, 95% CI 1.38-3.56, P = 0.001). The nomogram developed in this study exhibited good predictive capacity (area under the curve 0.742, 95% CI 0.679-0.804). The proposed model for predicting post-mandibulectomy TMJOA in patients with buccal or gingival cancer can identify high-risk individuals for early preventive oral rehabilitation., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest., (Copyright © 2024 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Chronic hepatitis B (CHB) leads to liver inflammation and dysfunction, resulting in liver fibrosis and cancer. Nucleos(t)ide analogues (NAs), inhibitors of hepatitis B virus (HBV), specifically suppress HBV replication. We proposed that immune modulation benefits seroconversion by HBsAg loss. However, activation of T lymphocytes also deteriorates hepatic inflammation. Therefore, we intended to investigate the T cell status and its relationship with hepatic functions in CHB patients treated with NAs. Serum markers, including liver function markers AST, ALT, and HBV-infected markers HBV DNA, HBsAg, HBeAg, and HBsAb were measured in the clinical routine. The T cell levels and markers, including CD69, CD107a, CXCR3, and PD-1 were investigated using flow cytometry. Meanwhile, IFNγ, IL-2, and CXCL10 as immune activation markers in the PBMCs were investigated using qPCR. To validate the effects of NAs on T cell status, qPCR and flow cytometry were used to investigate the gene expression in the HepG2 and PLC5 cells treated with NAs, and in the healthy PBMCs treated with the cell-cultured supernatant. We found that NAs significantly suppressed HBV DNA and reduced AST and ALT levels in the CHB patients. Meanwhile, AST and ALT were both positively correlated with activation marker CD107a in CD8 + T cells. In addition, we found that the CHB patients with seroconversion exhibited a higher CD4/CD8 ratio (p < 0.05) compared to non-seroconversion. We demonstrated that NAs potentially induced IFNs and PD-L1 expression in HepG2 and PLC5 cells. Moreover, the collected supernatant from NAs-treated HepG2 significantly activated PBMCs. This study revealed that the reduction of HBV by NAs may be the reason leading to less AST and ALT levels. We further demonstrated that NAs induced IFN expression in hepatic cells to potentially activate T lymphocytes, which was positively associated with AST and ALT levels in the CHB patients. The results may explain the phenomena in clinical that when the virus is reactivated by aborted use of NAs, it causes consequent T cells-mediated severe acute-on-chronic liver injury., (© 2024. The Author(s).)

Trastuzumab deruxtecan (T-DXd) is a human epidermal growth factor receptor 2 (HER2)-targeting antibody drug conjugate that has remarkable activity in HER2-positive cancers. However, the degree of benefit of T-DXd is not uniform among solid tumors even with high levels of HER2. Despite high HER2 expression, the HER2/T-DXd complex may not always undergo internalization and payload release dependent on the receptor's conformation and context. We hypothesize that epidermal growth factor receptor (EGFR), a dimerization partner of HER2, can modulate HER2 trafficking through endocytic pathways and affect T-DXd uptake. We demonstrate that elevated EGFR expression levels can promote EGFR/HER2 heterodimer formation and suppress T-DXd internalization and efficacy. Knockdown of EGFR expression or pharmacologic stimulation of EGFR endocytosis with EGFR monoclonal antibodies restores T-DXd trafficking and antitumor activity in EGFR-overexpressing cancers in vivo. Our results reveal EGFR overexpression to be a potential mechanism of resistance to T-DXd, which can be overcome by combination therapy strategies targeting EGFR., Competing Interests: Declaration of interests F.M. is employed by AstraZeneca and reports stock and other ownership interests from AstraZeneca. J.Z.D. reports research funding from AstraZeneca and consulting fees from AstraZeneca, Genagon, AmMax Bio, NuProbe, and Launchpad Therapeutics. S.T. and N.G. are employed by mProbe and report research funding, stock, and other ownership interests from mProbe. S.M. reports grants from Boehringer Ingelheim and Daiichi Sankyo and serves on the scientific advisory board of Bionseek. Y.Y.J. acknowledges research funding from the National Cancer Institute, Department of Defense, Cycle for Survival, Fred’s Team, Inspirna, AstraZeneca, Arcus Biosciences, Bayer, Genentech/Roche, Bristol-Myers Squibb, Eli Lilly, Merck, and Transcenta. She has served on advisory boards and/or done consulting for AbbVie, AmerisourceBergen, AskGene Pharma, Inc., Arcus Biosciences, Astellas, AstraZeneca, Basilea Pharmaceutica, Bayer, Bristol-Myers Squibb, Daiichi Sanyko, Eli Lilly, Geneos Therapeutics, GlaxoSmithKline, Guardant Health, Inc., Imedex, Imugene, Inspirna, Lynx Health, Merck, Merck Serono, Mersana Therapeutics, Pfizer, Seagen, Silverback Therapeutics, and Zymeworks, Inc., as well as Clinical Care Options, HMP Education, Michael J. Hennessy Associates, Paradigm Medical Communications, PeerView Institute, and Research to Practice. She also holds stock options in Inspirna. W.P. acknowledges research funding from the National Cancer Institute, Break Through Cancer, Parker Institute for Cancer Immunotherapy (PICI), Society for Immunotherapy of Cancer, The Society of MSK, Merck, Astellas, Miracogen, Amgen, and Revolution Medicines. He has served on advisory boards and/or done consulting for Astellas, EXACT Therapeutics, and Innovent Biologics. He has received honoraria for continuing medical education for American Physician Institute and Integrity. R.Y. has served as an advisor for Array BioPharma/Pfizer, Mirati Therapeutics, and Amgen; received a speaker’s honorarium from Zai Lab; and has received research support to her institution from Array BioPharma/Pfizer, Boehringer Ingelheim, Boundless Bio, Mirati Therapeutics, and Daiichi Sankyo. B.T.L. reports grants and other support from Amgen and grants from the NIH during the conduct of the study; grants and personal fees from Hengrui USA; grants and other support from Genentech Roche, Lilly, AstraZeneca, and Daiichi Sankyo; nonfinancial support and other support from Resolution Bioscience; grants and nonfinancial support from MORE Health; nonfinancial support from Jiangsu Hengrui Medicine; personal fees from Boehringer Ingelheim; grants from the NIH outside the submitted work; and a patent for US62/685,057 issued, a patent for US62/514,661 issued, royalties from Karger Publishers, and licensing with Shanghai Jiao Tong University Press. S.C. has received personal consulting fees from Novartis, AstraZeneca, Nuvalent, Genesis Therapeutics, eFFECTOR Therapeutics, SAGA Diagnostics, Prelude Therapeutics, and Casdin Capital. S.C. has research funding from AstraZeneca and Daiichi Sankyo., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

A range of challenges exists regarding vitreoretinal (VR) surgical services in resource-limited settings, including Sierra Leone. As a result, retinal pathologies may contribute to vision loss and blindness. In the wake of the 2013 to 2016 outbreak of Ebola virus disease in West Africa, gaps in ophthalmic care were underscored as survivors were experiencing a constellation of sequelae, including uveitis and VR disease. Given the unmet needs in addressing VR disease, systems for retinal surgical care were required. To further understand long-term ocular complications in Ebola survivors and molecular and immunologic factors associated with this, research infrastructure was developed for retinal evaluation and surgery. The 5 "S'" framework was implemented and considered staff, space, stuff, systems, and social support. The ongoing development of retinal health infrastructure has helped to address challenges related to program implementation, development of surgical capacity, and alignment with local stakeholders and collaborator objectives. VR surgical services have been established in Sierra Leone through multidisciplinary partnerships and collaboration and serve patients in-country, as well as others in West Africa who have traveled for care. Continued engagement across stakeholders can aim to address challenges and promote effective care delivery., Competing Interests: The authors declare that they have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: The initiative 2030 In Sight and the International Agency for the Prevention of Blindness have developed a plan to mitigate the global burden of preventable sight loss. One priority of this initiative is obtaining population eye health data. East Africa is a region that has historically been plagued by high rates of vision loss, and it is imperative to understand what causes are at play. Two large cross-sectional studies were previously published in 1995 and 2009, reporting the causes of childhood blindness (BL) and severe visual impairment (SVI) in East Africa. An update regarding more recent causes is warranted to better understand the trends of childhood BL/SVI in this region., Methods: A search strategy was developed a priori to identify relevant terms and align them with a standardized definition of East Africa. This strategy was then employed across PubMed, Google Scholar, and Scopus, with the yield of the overall search depicted in a Preferred Reporting Items for Systematic reviews and Meta-Analyses 2020 flow diagram. In the articles gathered by the search, causes of BL/SVI were typically categorized by anatomy and etiology., Results: Eight articles met the criteria, with data from 6 countries, consisting of 534 cases of childhood BL/SVI. Common anatomic locations identified included the cornea, lens, and whole globe. Among the most common etiologies were corneal scarring/opacity and cataract. Systemic etiologies and disease associations included measles, toxoplasmosis, and prematurity. Presumptive infectious disease and hereditary conditions were also identified as a category, but specific identification of etiologies and genetic diagnosis was largely unavailable., Conclusions: BL/SVI due to the cornea was among the common anatomic sites of disease in our study. The identification of measles as an associated systemic etiology requires further understanding in the context of increased vaccination programs. Multiple articles acknowledged that cataract has become the predominant cause of BL/SVI owing to increased measles vaccination and vitamin A supplementation. Additional research should be conducted to gain a complete understanding of childhood BL/SVI in East Africa, and responses at regional and national levels are likely necessary to address treatable causes of vision impairment., Competing Interests: The authors declare that they have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Phenotypic plasticity describes a genotype's ability to produce different phenotypes in response to different environments. Breeding crops that exhibit appropriate levels of plasticity for future climates will be crucial to meeting global demand, but knowledge of the critical environmental factors is limited to a handful of well-studied major crops. Using 727 maize (Zea mays L.) hybrids phenotyped for grain yield in 45 environments, we investigated the ability of a genetic algorithm and two other methods to identify environmental determinants of grain yield from a large set of candidate environmental variables constructed using minimal assumptions. The genetic algorithm identified pre- and postanthesis maximum temperature, mid-season solar radiation, and whole season net evapotranspiration as the four most important variables from a candidate set of 9150. Importantly, these four variables are supported by previous literature. After calculating reaction norms for each environmental variable, candidate genes were identified and gene annotations investigated to demonstrate how this method can generate insights into phenotypic plasticity. The genetic algorithm successfully identified known environmental determinants of hybrid maize grain yield. This demonstrates that the methodology could be applied to other less well-studied phenotypes and crops to improve understanding of phenotypic plasticity and facilitate breeding crops for future climates., (© 2024 The Author(s). New Phytologist © 2024 New Phytologist Foundation. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: Dupilumab, an antibody that binds IL-4Rα and inhibits IL-4 and IL-13 signals, has demonstrated efficacy in chronic rhinosinusitis with nasal polyps (CRSwNP) primarily characterized by type 2 inflammation. Current evidence suggests that the rate of improvement in olfactory dysfunction with dupilumab exceeds that of nasal polyp reduction, yet the underlying mechanism remains undisclosed. We hypothesize that dupilumab may initially ameliorate sensorineural olfactory dysfunction., Methodology: Male BALB/c mice were intranasally administered ovalbumin and Aspergillus protease for 12 weeks to induce eosinophilic sinonasal inflammation. Dupilumab treatment was also administered. The mice underwent histological assessment, olfactory behavioural test, and gene expression profiling to identify neuroinflammatory markers within the olfactory bulb., Results: Dupilumab treatment resulted in a reduction in the number of mucosal protruding lesions, as well as decreased infiltration of eosinophils and neutrophils, along with a decrease in olfactory sensory neuron injury. Furthermore, there was a downregulation in the mRNA expression related to microglia activation and neuroinflammation in the olfactory bulb., Conclusions: Dupilumab improves the sensorineural pattern of olfactory dysfunction in mice, potentially explaining why olfaction improves more rapidly than polyp reduction in patients with CRSwNP.

Introduction: Studies suggest that patients are satisfied with telehealth in ambulatory settings. However, tele-neurology satisfaction data are limited by a small sample size and COVID-19-era data is not specific to movement disorders clinics. In this prospective observational study, telehealth utilization during the COVID-19 pandemic was assessed, and patient satisfaction was compared between telehealth and in-person visits in an outpatient movement disorders center., Methods: Patients ≥18 years who completed an appointment at Northwestern's Movement Disorders Clinic were invited to complete a post-visit Medallia survey. The primary outcomes of the survey were likelihood to recommend (LTR) provider, LTR location, and 'spent enough time,' on a 0-10 scale. Responses were categorized into in-person vs. telehealth groups., Results: Telehealth utilization significantly increased from a pre-COVID timeframe rate of 0.3% (Nov 2019 to Feb 2020) to 39.5% during the COVID-19 pandemic (March 2020 through April 2021) ( p -value < 0.001). During the COVID-19 pandemic, 621 patients responded to the post-visit Medallia survey (response rate = 30%), including 365 in-person and 256 telehealth visits. No significant differences were observed between in-person and telehealth encounters in LTR provider ( p  = 0.892), LTR location ( p  = 0.659), and time spent ( p  = 0.395). Additional subgroup multivariable analysis did not support differences in satisfaction between different age groups., Discussion: With its large sample size, our study demonstrates that in the setting of increased TH utilization in movement disorders clinic during the COVID-19 pandemic, patients reported similar satisfaction with telehealth compared to in-person visits. This study supports the utility of telehealth to provide specialized neurologic clinic care., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Human T-cell leukemia virus type 1 (HTLV-I) is the etiological agent of adult T-cell leukemia (ATL). Mutational analysis has demonstrated that the tumor suppressor, F-box and WD repeat domain containing 7 (FBXW7/FBW7/CDC4), is mutated in primary ATL patients. However, even in the absence of genetic mutations, FBXW7 substrates are stabilized in ATL cells, suggesting additional mechanisms can prevent FBXW7 functions. Here, we report that the viral oncoprotein Tax represses FBXW7 activity, resulting in the stabilization of activated Notch intracellular domain, c-MYC, Cyclin E, and myeloid cell leukemia sequence 1 (BCL2-related) (Mcl-1). Mechanistically, we demonstrate that Tax directly binds to FBXW7 in the nucleus, effectively outcompeting other targets for binding to FBXW7, resulting in decreased ubiquitination and degradation of FBXW7 substrates. In support of the nuclear role of Tax, a non-degradable form of the nuclear factor kappa B subunit 2 (NFκB2/p100) was found to delocalize Tax to the cytoplasm, thereby preventing Tax interactions with FBXW7 and Tax-mediated inhibition of FBXW7. Finally, we characterize a Tax mutant that is unable to interact with FBXW7, unable to block FBXW7 tumor suppressor functions, and unable to effectively transform fibroblasts. These results demonstrate that HTLV-I Tax can inhibit FBXW7 functions without genetic mutations to promote an oncogenic state. These results suggest that Tax-mediated inhibition of FBXW7 is likely critical during the early stages of the cellular transformation process., Importance: F-box and WD repeat domain containing 7 (FBXW7), a critical tumor suppressor of human cancers, is frequently mutated or epigenetically suppressed. Loss of FBXW7 functions is associated with stabilization and increased expression of oncogenic factors such as Cyclin E, c-Myc, Mcl-1, mTOR, Jun, and Notch. In this study, we demonstrate that the human retrovirus human T-cell leukemia virus type 1 oncoprotein Tax directly interacts with FBXW7, effectively outcompeting other targets for binding to FBXW7, resulting in decreased ubiquitination and degradation of FBXW7 cellular substrates. We further demonstrate that a Tax mutant unable to interact with and inactivate FBXW7 loses its ability to transform primary fibroblasts. Collectively, our results describe a novel mechanism used by a human tumor virus to promote cellular transformation., Competing Interests: The authors declare no conflict of interest.

Background: Although the postpartum period is an opportunity to address long-term health, fragmented care systems, inadequate attention to social needs, and a lack of structured transition to primary care threaten patient wellbeing, particularly for low-income individuals. Postpartum patient navigation is an emerging innovation to address these disparities. Methods: This mixed-methods analysis uses data from the first year of an ongoing randomized controlled trial to understand the needs of low-income postpartum individuals through 1 year of patient navigation. We designed standardized logs for navigators to record their services, tracking mode, content, intensity, and target of interactions. Navigators also completed semistructured interviews every 3 months regarding relationships with patients and care teams, care system gaps, and navigation process. Log data were categorized, quantified, and mapped temporally through 1 year postpartum. Qualitative data were analyzed using the constant comparative method. Results: Log data from 50 participants who received navigation revealed the most frequent needs related to health care access (45.4%), health and wellness (18.2%), patient-navigator relationship building (14.8%), parenting (13.6%), and social determinants of health (8.0%). Navigation activities included supporting physical and mental recovery, accomplishing health goals, connecting patients to primary and specialty care, preparing for health system utilization beyond navigation, and referring individuals to community resources. Participant needs fluctuated, yielding a dynamic timeline of the first postpartum year. Conclusion: Postpartum needs evolved throughout the year, requiring support from various teams. Navigation beyond the typical postpartum care window may be useful in mitigating health system barriers, and tracking patient needs may be useful in optimizing postpartum care. Clinical Trial Registration: Registered April 19, 2019, enrollment beginning January 21, 2020, NCT03922334, https://clinicaltrials.gov/ct2/show/NCT03922334.

The COVID-19 pandemic has changed many facets of medical care and has resulted in a rise in delayed treatments across all specialties, including cosmetic dermatology. Delayed care for squamous cell carcinomas (SCC) and basal cell carcinoma (BCC) is not only a burden for medical providers, but also confers a risk to patients, as delayed surgeries are associated with increased metastatic risk and tumor size. Mohs micrographic surgery (MMS) delayed by more than one year leads to increased risk of complications, including bleeding and impaired wound healing, especially in the elderly population. To decrease bleeding risks, we have developed a modified MMS technique known as the "rim and deep margin" technique. Here, we present additional cases using this technique to minimize bleeding and operative time for patients with an increased risk of morbidity. This technique has been used successfully in the past for large tumors and can now be used for patients who have faced delay of care, as evidenced by its success during the COVID-19 pandemic., Competing Interests: DISCLOSURES: The authors have no conflicts of interest relevant to the content of this article., (Copyright © 2024. Matrix Medical Communications. All rights reserved.)

Pressure ulcers (PUs) are economically burdensome medical conditions. Early changes in pressure ulcers are associated with erythema. In this study, bioelectrical impedance was used to measure the differences between PUs and blanchable erythema. We divided 21 ICR mice into three groups: control, 1000 mmHg-1h, and 1000 mmHg-6h. Healthy skin, blanchable erythema, and PUs were induced on the dorsal skin. The results indicated an immediate increase in impedance, resistance, and reactance values in the pressure group after release, followed by a subsequent decrease until two days after release. Compared with the control group, impedance and reactance significantly increased by 30.9% (p < 0.05) and 30.1% (p < 0.01), respectively, in the 6 h-loading group immediately after release. One and two days after release, the 1 h-loading and 6 h-loading groups exhibited significantly different degrees of decline. One day after release, impedance and resistance decreased by 30.2% (p < 0.05) and 19.8% (p < 0.05), respectively, in the 1 h-loading group; while impedance, resistance, and reactance decreased by 39.2% (p < 0.01), 26.8% (p < 0.01), and 45.7% (p < 0.05), respectively, in the 6 h-loading group. Two days after release, in the 1 h-loading group, impedance and resistance decreased by 28.3% (p < 0.05) and 21.7% (p < 0.05), respectively; while in the 6 h-loading group, impedance, resistance, and reactance decreased by 49.8% (p < 0.001), 34.2% (p < 0.001), and 59.8% (p < 0.01), respectively. One and two days after release the pressure group reductions were significantly greater than those in the control group. Additionally, we monitored changes during wound healing. Distinguishing early PUs from blanchable erythema by noninvasive bioelectrical impedance technology may have applications value in early assessment of PUs., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Tissue Viability Society / Society of Tissue Viability. Published by Elsevier Ltd. All rights reserved.)

Background: Neighborhood physical environments may influence cardiometabolic health, but prior studies have been inconsistent, and few included long follow-up periods., Methods: Changes in cardiometabolic risk factors were measured for up to 14 years in 2830 midlife women in the Study of Women's Health Across the Nation, a multi-ethnic/racial cohort of women from seven U.S. sites. Data on neighborhood food retail environments (modified Retail Food Environment Index) and walkability (National Walkability Index) were obtained for each woman's residence at each follow-up. Data on neighborhood access to green space, parks, and supermarkets were available for subsets (32-42%) of women. Models tested whether rates of change in cardiometabolic outcomes differed based on neighborhood characteristics, independent of sociodemographic and health-related covariates., Results: Living in more (vs. less) walkable neighborhoods was associated with favorable changes in blood pressure outcomes (SBP: -0.27 mmHg/year, p = 0.002; DBP: -0.22 mmHg/year, p < 0.0001; hypertension status: ratio of ORs = 0.79, p < 0.0001), and small declines in waist circumference (-0.09 cm/year, p = 0.03). Small-magnitude associations were also observed between low park access and greater increases in blood pressure outcomes (SBP: 0.37 mmHg/year, p = 0.003; DBP: 0.15 mmHg/year, p = 0.04; hypertension status: ratio of ORs = 1.16, p = .04), though associations involving DBP and hypertension were only present after adjustment for sociodemographic variables. Other associations were statistically unreliable or contrary to hypotheses., Conclusion: Neighborhood walkability may have a meaningful influence on trajectories of blood pressure outcomes in women from midlife to early older adulthood, suggesting the need to better understand how individuals interact with their neighborhood environments in pursuit of cardiometabolic health., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: To evaluate the association between embryo transfer techniques and pregnancy outcomes., Design: This is a prospective observational study with a retrospective cohort., Setting: University Clinic., Patients: Patients underwent embryo transfers between 2015 and 2020., Intervention/exposure: Fourteen physicians performed 25 mock embryo transfers on the embryo transfer simulator and completed a questionnaire assessing preferred embryo transfer techniques. Quantitative performance metrics on the embryo transfer simulator were measured. Individual physician embryo transfer success rates were retrospectively collected from all fresh and cryopreserved embryo transfers between January 1, 2015, and January 1, 2020. Associations between embryo transfer techniques (preferred technique and simulator performance metrics) and each physician's historical patient pregnancy outcomes were assessed., Main Outcome Measures: Associations between embryo transfer techniques and live births were assessed., Results: There were significant differences in embryo transfer techniques between physicians, including touches to the fundus, distance to the fundus, duration of embryo transfer, duration of the complete procedure, time spent navigating the cervical canal, velocity of embryo expulsion, time waited after embryo expulsion, and total score on the embryo transfer simulator. After controlling for confounders and multiple transfers per physician, the duration of embryo transfer was significantly associated with live birth, with longer durations associated with decreased live birth rates. Shorter placement distance to the fundus and higher velocity of embryo expulsion were both significantly associated with higher rates of ectopic pregnancy., Conclusions: This study revealed significant differences in transfer techniques among physicians. The use of the embryo transfer simulator for physicians in practice can elucidate differences and create opportunities for data-driven improvement in embryo transfer success rates., Competing Interests: D.B.M. has nothing to disclose. A.B. has nothing to disclose. C.Y. has nothing to disclose. S.D. has nothing to disclose. M.P.M. has nothing to disclose. E.C.F. has nothing to disclose., (© 2024 The Authors.)

Pyridoxal 5'-phosphate (PLP)-dependent enzymes that catalyze γ-replacement reactions are prevalent, yet their utilization of carbon nucleophile substrates is rare. The recent discovery of two PLP-dependent enzymes, CndF and Fub7, has unveiled unique C-C bond forming capabilities, enabling the biocatalytic synthesis of alkyl- substituted pipecolic acids from O-acetyl-L-homoserine and β-keto acid or aldehyde derived enolates. This breakthrough presents fresh avenues for the biosynthesis of pipecolic acid derivatives. However, the catalytic mechanisms of these enzymes remain elusive, and a dearth of structural information hampers their extensive application. Here, we have broadened the catalytic scope of Fub7 by employing ketone-derived enolates as carbon nucleophiles, revealing Fub7's capacity for substrate-dependent regioselective α-alkylation of unsymmetrical ketones. Through an integrated approach combining X-ray crystallography, spectroscopy, mutagenesis, and computational docking studies, we offer a detailed mechanistic insight into Fub7 catalysis. Our findings elucidate the structural basis for its substrate specificity, stereoselectivity, and regioselectivity. Our work sets the stage ready for subsequent protein engineering effort aimed at expanding the synthetic utility of Fub7, potentially unlocking novel methods to access a broader array of noncanonical amino acids., (© 2024 Wiley-VCH GmbH.)

Background: Understanding why some triple-negative breast cancer (TNBC) patients respond poorly to existing therapies while others respond well remains a challenge. This study aims to understand the potential underlying mechanisms distinguishing early-stage TNBC tumors that respond to clinical intervention from non-responders, as well as to identify clinically viable therapeutic strategies, specifically for TNBC patients who may not benefit from existing therapies., Methods: We conducted retrospective bioinformatics analysis of historical gene expression datasets to identify a group of genes whose expression levels in early-stage tumors predict poor clinical outcomes in TNBC. In vitro small-molecule screening, genetic manipulation, and drug treatment in syngeneic mouse models of TNBC were utilized to investigate potential therapeutic strategies and elucidate mechanisms of drug action., Results: Our bioinformatics analysis reveals a robust association between increased expression of immunosuppressive cytokine S100A8/A9 in early-stage tumors and subsequent disease progression in TNBC. A targeted small-molecule screen identifies PIM kinase inhibitors as capable of decreasing S100A8/A9 expression in multiple cell types, including TNBC and immunosuppressive myeloid cells. Combining PIM inhibition and immune checkpoint blockade induces significant antitumor responses, especially in otherwise resistant S100A8/A9-high PD-1/PD-L1-positive tumors. Notably, serum S100A8/A9 levels mirror those of tumor S100A8/A9 in a syngeneic mouse model of TNBC., Conclusions: Our data propose S100A8/A9 as a potential predictive and pharmacodynamic biomarker in clinical trials evaluating combination therapy targeting PIM and immune checkpoints in TNBC. This work encourages the development of S100A8/A9-based liquid biopsy tests for treatment guidance., (© 2024. The Author(s).)

Childhood blindness is an issue of global health impact, affecting approximately 2 million children worldwide. Vision 2020 and the United Nations Sustainable Development Goals previously identified childhood blindness as a key issue in the twentieth century, and while public health measures are underway, the precise etiologies and management require ongoing investigation and care, particularly within resource-limited settings such as sub-Saharan Africa. We systematically reviewed the literature on childhood blindness in West Africa to identify the anatomic classification and etiologies, particularly those causes of childhood blindness with systemic health implications. Treatable causes included cataract, refractive error, and corneal disease. Systemic etiologies identified included measles, rubella, vitamin A deficiency, and Ebola virus disease. While prior public health measures including vitamin A supplementation and vaccination programs have been deployed in most countries with reported data, multiple studies reported preventable or reversible etiologies of blindness and vision impairment. Ongoing research is necessary to standardize reporting for anatomies and/or etiologies of childhood blindness to determine the necessity of further development and implementation of public health measures that would ameliorate childhood blindness and vision impairment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yeh, Huang, Huang, Hartley, Fashina, Ashby, Miller, Shantha, Justin, Chan, Mattia, Vandy, Harrison-Williams, Mustapha, Mwanza and Yeh.)

Purpose: There remains a need for novel therapies for patients with metastatic breast cancer (MBC). We explore the use of a novel biomarker of survival that could potentially expedite the testing of novel therapies., Methods: We applied a tumor regression-growth model to radiographic measurement data from 393 women with MBC enrolled in PALOMA-3 examining efficacy of palbociclib in disease that had progressed on previous endocrine therapy. 261 and 132 women were randomized to fulvestrant plus palbociclib or placebo, respectively. We estimated rates of regression (d) and growth (g) of the sensitive and resistant fractions of tumors, respectively. We compared the median g of both arms. We examined the relationship between g and progression-free and overall survival (OS)., Results: As in other tumors, g is a biomarker of OS. In PALOMA-3, we found significant differences in g among patients with tumors sensitive to endocrine therapy but not amongst resistant tumors, emulating clinical trial results. Subgroup analysis found favorable g values in visceral metastases treated with palbociclib. Palbociclib efficacy demonstrated by slower g values was evident early in the trial, twelve weeks after the first 28 patients had been enrolled., Conclusion: Values of g, estimated using data collected while a patient is enrolled in a clinical trial is an excellent biomarker of OS. Our results correlate with the survival outcomes of PALOMA-3 and argue strongly for using g as a clinical trial endpoint to help inform go/no-go decisions, improve trial efficiency, and deliver novel therapies to patients sooner., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Transformer models are revolutionizing machine learning, but their inner workings remain mysterious. In this work, we present a new visualization technique designed to help researchers understand the self-attention mechanism in transformers that allows these models to learn rich, contextual relationships between elements of a sequence. The main idea behind our method is to visualize a joint embedding of the query and key vectors used by transformer models to compute attention. Unlike previous attention visualization techniques, our approach enables the analysis of global patterns across multiple input sequences. We create an interactive visualization tool, AttentionViz (demo: http://attentionviz.com), based on these joint query-key embeddings, and use it to study attention mechanisms in both language and vision transformers. We demonstrate the utility of our approach in improving model understanding and offering new insights about query-key interactions through several application scenarios and expert feedback.

Background: Social determinants of health are important contributors to maternal and child health outcomes. Limited existing research examines the relationship between housing instability during pregnancy and perinatal care utilization. Our objective was to evaluate whether antenatal housing instability is associated with differences in perinatal care utilization and outcomes. Materials and Methods: Participants who were surveyed during their postpartum hospitalization were considered to have experienced housing instability if they answered affirmatively to at least one of six screening items. The primary outcome was adequacy of prenatal care measured by the Adequacy of Prenatal Care Utilization index. Maternal, neonatal, and postpartum outcomes, including utilization and breastfeeding, were also collected as secondary outcomes. Multivariable logistic regression models were adjusted for sociodemographic and clinical covariates. Results: In this cohort ( N  = 490), 11.2% ( N  = 55) experienced housing instability during pregnancy. Participants with unstable housing were more likely to have inadequate prenatal care (17.3% vs. 3.9%; odds ratio [OR] 5.11, 95% confidence interval [CI] 2.15-12.14, p  < 0.001), but findings were not significant after adjustment (aOR 1.72, 95% CI 0.55-5.41, p  = 0.35). Similarly, postpartum visit attendance was lower for individuals with unstable housing (79.6% vs. 91.2%), but there was no difference in the odds of the postpartum visit attendance after adjustment (OR 0.69, 95% CI 0.29-1.66, p  = 0.14). Conclusions: There were no statistically significant association with the maternal, neonatal, and other postpartum secondary outcomes. Housing instability appears to be a risk marker that is related to other social determinants of health. Given the range of housing instability experiences, future research must account for specific types and degrees of housing instability and their potential perinatal consequences.