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Abstract Background SETBP1 Haploinsufficiency Disorder (SETBP1-HD) is characterised by mild to moderate intellectual disability, speech and language impairment, mild motor developmental delay, behavioural issues, hypotonia, mild facial dysmorphisms, and vision impairment. Despite a clear link between SETBP1 mutations and neurodevelopmental disorders the precise role of SETBP1 in neural development remains elusive. We investigate the functional effects of three SETBP1 genetic variants including two pathogenic mutations p.Glu545Ter and SETBP1 p.Tyr1066Ter, resulting in removal of SKI and/or SET domains, and a point mutation p.Thr1387Met in the SET domain. Methods Genetic variants were introduced into induced pluripotent stem cells (iPSCs) and subsequently differentiated into neurons to model the disease. We measured changes in cellular differentiation, SETBP1 protein localisation, and gene expression changes. Results The data indicated a change in the WNT pathway, RNA polymerase II pathway and identified GATA2 as a central transcription factor in disease perturbation. In addition, the genetic variants altered the expression of gene sets related to neural forebrain development matching characteristics typical of the SETBP1-HD phenotype. Limitations The study investigates changes in cellular function in differentiation of iPSC to neural progenitor cells as a human model of SETBP1 HD disorder. Future studies may provide additional information relevant to disease on further neural cell specification, to derive mature neurons, neural forebrain cells, or brain organoids. Conclusions We developed a human SETBP1-HD model and identified perturbations to the WNT and POL2RA pathway, genes regulated by GATA2. Strikingly neural cells for both the SETBP1 truncation mutations and the single nucleotide variant displayed a SETBP1-HD-like phenotype.

Abstract Current KRASG12C (OFF) inhibitors that target inactive GDP-bound KRASG12C cause responses in less than half of patients and these responses are not durable. A class of RASG12C (ON) inhibitors that targets active GTP-bound KRASG12C blocks ERK signaling more potently than the inactive-state inhibitors. Sensitivity to either class of agents is strongly correlated with inhibition of mTORC1 activity. We have previously shown that PI3K/mTOR and ERK-signaling pathways converge on key cellular processes and that inhibition of both pathways is required for inhibition of these processes and for significant antitumor activity. We find here that the combination of a KRASG12C inhibitor with a selective mTORC1 kinase inhibitor causes synergistic inhibition of Cyclin D1 expression and cap-dependent translation. Moreover, BIM upregulation by KRASG12C inhibition and inhibition of MCL-1 expression by the mTORC1 inhibitor are both required to induce significant cell death. In vivo, this combination causes deep, durable tumor regressions and is well tolerated. This study suggests that the ERK and PI3K/mTOR pathways each mitigate the effects of inhibition of the other and that combinatorial inhibition is a potential strategy for treating KRASG12C-dependent lung cancer.

Chronic diseases are the leading cause of death and disability in the United States, and much of this burden can be attributed to lifestyle and behavioral risk factors. Lifestyle medicine is an approach to preventing and treating lifestyle-related chronic disease using evidence-based lifestyle modification as a primary modality. NYC Health + Hospitals, the largest municipal public health care system in the United States, is a national pioneer in incorporating lifestyle medicine systemwide. In 2019, a pilot lifestyle medicine program was launched at NYC Health + Hospitals/Bellevue to improve cardiometabolic health in high-risk patients through intensive support for evidence-based lifestyle changes. Analyses of program data collected from January 29, 2019 to February 26, 2020 demonstrated feasibility, high demand for services, high patient satisfaction, and clinically and statistically significant improvements in cardiometabolic risk factors. This pilot is being expanded to 6 new NYC Health + Hospitals sites spanning all 5 NYC boroughs. As part of the expansion, many changes have been implemented to enhance the original pilot model, scale services effectively, and generate more interest and incentives in lifestyle medicine for staff and patients across the health care system, including a plant-based default meal program for inpatients. This narrative review describes the pilot model and outcomes, the expansion process, and lessons learned to serve as a guide for other health systems.

Summary: Autism spectrum disorder (ASD) is a neurodevelopmental disorder (NDD) that affects approximately 4% of males and 1% of females in the United States. While causes of ASD are multi-factorial, single rare genetic variants contribute to around 20% of cases. Here, we report a case series of seven unrelated probands (6 males, 1 female) with ASD or another variable NDD phenotype attributed to de novo heterozygous loss of function or missense variants in the gene LARP1 (La ribonucleoprotein 1). LARP1 encodes an RNA-binding protein that post-transcriptionally regulates the stability and translation of thousands of mRNAs, including those regulating cellular metabolism and metabolic plasticity. Using lymphocytes collected and immortalized from an index proband who carries a truncating variant in one allele of LARP1, we demonstrated that lower cellular levels of LARP1 protein cause reduced rates of aerobic respiration and glycolysis. As expression of LARP1 increases during neurodevelopment, with higher levels in neurons and astrocytes, we propose that LARP1 haploinsufficiency contributes to ASD or related NDDs through attenuated metabolic activity in the developing fetal brain.

A 20-year-old man with metastatic large cell neuroendocrine carcinoma of the lung was treated with the delta-like ligand 3–targeting bispecific T cell engager, tarlatamab. Treatment was complicated by transient cytokine release syndrome but resulted in a partial response. Bispecific T cell engagers may offer a novel treatment approach for large cell neuroendocrine carcinoma of the lung.

PURPOSEThe early phase of the COVID-19 pandemic affected cancer care globally. Evaluating the impact of the pandemic on the quality of cancer care delivery is crucial for understanding how changes in care delivery may influence outcomes. Our study compared care delivered during the early phase of the pandemic with the same period in the previous year at two institutions across continents (Princess Margaret Cancer Center [PM] in Canada and A.C. Camargo Cancer Center [AC] in Brazil).METHODSPatients newly diagnosed with colorectal or anal cancer between February and December 2019 and the same period in 2020 were analyzed. Sociodemographic and clinical characteristics and performance of individual indicators within and between centers and between the peri–COVID-19 and control cohorts were tested using Cohen's h test to assess the standardized differences between the two groups.RESULTSAmong 925 patients, distinct effects of the early COVID-19 pandemic on oncology services were observed. AC experienced a 50% reduction in patient consultations (98 v 197) versus a 12.5% reduction at PM (294 v 336). Similarly, AC experienced a higher proportion of stage IV disease presentations (42.9% v 29.9%; P = .015) and an increase in treatment delay (61.9% v 9.7%; P < .001) compared with prepandemic. At PM, a 10% increase in treatment interruption (32.4% v 22.3%; P < .001) and a higher rate of discontinuation of radiotherapy (9.4% v 1.1%; P < .001) were observed during the pandemic. Postsurgical readmission rates increased in both AC (20.9% v 2.6%; P < .001) and PM (10.5% v 3.6%; P < .01).CONCLUSIONThe early phase of the COVID-19 pandemic affected the quality of care delivery for colorectal and anal cancers at both centers. However, the magnitude of this impact was greater in Brazil.

Background Collateral status (CS) plays a crucial role in infarct growth rate, risk of postthrombectomy hemorrhage, and overall clinical outcomes in patients with acute ischemic stroke (AIS) secondary to anterior circulation large‐vessel occlusions (LVOs). Hypoperfusion intensity ratio has been previously validated as an indirect noninvasive pretreatment imaging biomarker of CS. In addition to imaging, derangements in admission laboratory findings can also influence outcomes in patients with AIS‐LVO. Therefore, our study aims to assess the relationship between admission laboratory findings, baseline characteristics, and CS, as assessed by hypoperfusion intensity ratio in patients with AIS‐LVO. Methods and Results In this retrospective study, consecutive patients presenting with AIS secondary to anterior circulation LVO who underwent pretreatment computed tomography perfusion were included. The computed tomography perfusion data processed by RAPID (Ischema View, Menlo Park, CA) generated the hypoperfusion intensity ratio. Binary logistic regression models were used to assess the relationship between patients' baseline characteristics, admission laboratory findings, and poor CS. A total of 221 consecutive patients with AIS‐LVO between January 2017 and September 2022 were included in our study (mean±SD age, 67.0±15.8 years; 119 men [53.8%]). Multivariable logistic regression showed that patients with AIS caused by cardioembolic and cryptogenic causes (adjusted odds ratio [OR], 2.67; 95% CI, 1.20–5.97; P=0.016), those who presented with admission National Institutes of Health Stroke Scale score ≥12 (adjusted OR, 3.12; 95% CI, 1.61–6.04; P=0.001), and male patients (adjusted OR, 2.06; 95% CI, 1.13–3.77; P=0.018) were associated with poor CS. Conclusions Stroke caused by cardioembolic or cryptogenic causes, admission National Institutes of Health Stroke Scale score of ≥12, and male sex were associated with poor CS, as defined by hypoperfusion intensity ratio in the patients with AIS‐LVO.

We undertook a retrospective study to compare the quality of care delivered to a cohort of newly diagnosed adults with colon, rectal or anal cancer during the early phase of COVID-19 (02/20–12/20) relative to the same period in the year prior (the comparator cohort), and examine the impact of the pandemic on 2-year disease progression and all-cause mortality. We observed poorer performance on a number of quality measures, such as approximately three times as many patients in the COVID-19 cohort experienced 30-day post-surgical readmission (10.5% vs. 3.6%; SD:0.27). Despite these differences, we observed no statistically significant adjusted associations between COVID-19 and time to either all-cause mortality (HR: 0.88, 95% CI: 0.61–1.27, p = 0.50) or disease progression (HR: 1.16, 95% CI: 0.82–1.64, p = 0.41). However, there was a substantial reduction in new patient consults during the early phase of COVID-19 (12.2% decrease), which appeared to disproportionally impact patients who traditionally experience sociodemographic disparities in access to care, given that the COVID-19 cohort skewed younger and there were fewer patients from neighborhoods with the highest Housing and Dwelling, ands Age and Labour Force marginalization quintiles. Future work is needed to understand the more downstream effects of COVID-19 related changes on cancer care to inform planning for future disruptions in care.

Background:. Scrubs have become widespread office attire for plastic surgeons. The purpose of this study is to evaluate the public perception of scrub color and style for plastic surgeons. Methods:. A crowdsourced survey was performed via MTurk. Respondents were asked to rate images of a surgeon dressed in black, navy, blue, and green scrubs as well as traditional or fitted scrubs. Qualities including representativeness, skill, trustworthiness, knowledge, and compassion were rated on a Likert scale across all images. Analysis of variance and one-sided t test were used to analyze differences in means. Results:. In total, 562 responses were collected. For female plastic surgeons, navy and blue scrubs were perceived to be superior to those wearing black for skill, representativeness, trustworthiness, and compassion (P < 0.05). For male plastic surgeons, navy and blue scrubs were superior to black for knowledge, skill, representativeness, trustworthiness, and compassion (P < 0.05). For skill and representativeness, navy was superior to green (P < 0.05). For representativeness, blue was superior to green (P < 0.05). For trustworthiness and compassion, green was superior to black (P < 0.05). Fitted scrubs were significantly preferred (P < 0.05) across all characteristics with the exception of representativeness in the subgroup of male plastic surgeons. Conclusions:. Black scrubs are associated with more negative characteristics than navy or blue scrubs, which were found to be the most positively perceived. Fitted scrubs were associated with positive characteristics for both male and female surgeons. The purchase of fitted scrubs may be a worthwhile purchase to maximize the patient–physician relationship.

Summary: Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant disease with a poor prognosis due to inefficient diagnosis and tenacious drug resistance. Obg-like ATPase 1 (OLA1) is overexpressed in many malignant tumors. The molecular mechanism of OLA1 underlying gemcitabine (GEM)-induced drug resistance was investigated in this study. An enhanced expression of OLA1 was observed in a GEM acquired resistant pancreatic cancer cell lines and in patients with pancreatic cancer. Overexpressed OLA1 showed poor overall survival rates in patients with pancreatic cancer. Dysregulation of the OLA1 reduced expression of CD44+/CD133+, and improved the sensitivity of pancreatic cancer cells to GEM. OLA1 highly expression facilitated the formation of the OLA1/Sonic Hedgehog (SHH)/Hedgehog-interacting protein (HHIP) complex in nuclei, resulting in the inhibition of negative feedback of Hedgehog signaling induced by HHIP. This study suggests that OLA1 may be developed as an innovative drug target for an effective therapy of pancreatic cancer.

Understanding differences in how demographic groups experience telehealth may be relevant in addressing potential disparities in telehealth usage. We seek to identify and examine themes most pertinent to patients’ negative telehealth experiences by age and race in order to inform interventions to improve patients’ future telehealth experiences. We performed a content analysis of Press Ganey patient experience surveys from adult patients at 17 primary care sites of a large, public healthcare system with visits from April 30, 2020 to August 27, 2021. We used sentiment analysis to identify negative comments. We coded for content themes and analyzed their frequency, stratifying by age and race. We analyzed 745 negative comments. Most frequent themes differed by demographic categories, but overall, the most commonly applied codes were “Contacting the Clinic” (n = 97), “Connectivity” (n = 84), and “Webside Manner” (n = 79). The top three codes accounted for >40% of the negative codes in each race category and >35% of the negative codes in each age category. While there were common negative experiences among groups, patients of different demographics highlighted different aspects of their telehealth experiences for potential improvement.

Background: End-stage renal disease (ESRD) and renal transplant (RT) patients are known to have more perioperative and postoperative complications after arthroplasty surgeries when compared to patients without. We hypothesize that RT patients undergoing shoulder arthroplasty (SA) have fewer systemic and surgical complications when compared to ESRD patients undergoing SA. Methods: This was a retrospective review from the PearlDiver Patient Record Database. International Classification of Diseases and Current Procedural Terminology codes were used to identify patients who had undergone primary total and reverse shoulder arthroplasty, respectively, and subsequent surgical revisions. Unadjusted univariate analysis of patient demographics, Charlson Cormorbidty Index, and surgical complications at 90 days, 1 year, and 2 years after was performed using chi-squared testing. Multivariate logistic regression analyses were subsequently performed for systemic complications and prosthesis outcomes at all time points. Results: Of 1191 patients with ESRD or previous RT and who underwent either total shoulder arthroplasty or reverse total shoulder arthroplasty, 1042 (87.5%) had ESRD and 149 (12.5%) had a previous RT. ESRD SA patients were more likely to have hypertension, liver disease, coronary artery disease, and hypothyroidism. Interestingly no statistical significance was found in multivariate analysis for systemic complications at 90 days, nor for surgical complications at the 90-day, 1-year, or 2-year mark between ESRD and RT cohorts. Conclusion: SAs have comparable outcomes in ESRD and RT patients. The differing conclusions among studies might be partially accounted for by the demographic differences and comorbidities between these 2 patient populations. Providers should continue to provide appropriate counseling concerning risks, benefits, and timing of SA for these patients.

Introduction: Patients and clinicians face challenges in participating in video telehealth visits. Patient navigation has been effective in other settings in enhancing patients’ engagement with clinical programs. Our objective was to assess whether implementing a telehealth navigator program to support patients and clinicians affected video visit scheduling, video usage, and non-attendance. Methods: This was a quasi-experimental quality improvement project using difference-in-differences. We included data from 17 adult primary care sites at a large, urban public healthcare system from October 1, 2021 to October 31, 2022. Six sites received telehealth navigators and 11 sites were used as comparators. Navigators contacted patients (by phone) with upcoming video visits to assess and address potential barriers to successful video visit completion. They also provided on-site support to patients and clinicians regarding telehealth visits and usage of an electronic patient portal. The primary outcomes were difference-in-differences for the proportion of telehealth visits scheduled and, separately, completed as video visits and non-attendance for visits scheduled as video visits. Results: There were 65 488 and 71 504 scheduled telehealth appointments at intervention and non-intervention sites, respectively. The adjusted difference-in-differences for the proportion of telehealth visits scheduled as video was −9.1% [95% confidence interval −26.1%, 8.0%], the proportion of telehealth visits completed as video visits 1.3% [−4.9%, 7.4%], and non-attendance for visits scheduled as video visits −3.7% [−6.0%, −1.4%]. Conclusions: Sites with telehealth navigators had comparatively lower video visit non-attendance but did not have comparatively different video visit scheduling or completion rates. Despite this, navigators’ on-the-ground presence can help identify opportunities for improvements in care design.

This study examines whether patients’ telehealth experiences differed during a health system mandate for telehealth encounters due to the COVID-19 pandemic versus after the mandate was relaxed. Patient experience surveys from telehealth visits across 17 adult (age 18+) primary care sites at a large, urban public health system were analyzed during two periods: when a mandate was active (March 1, 2020-June 30, 2020) and when the mandate was relaxed and any appointment modality was available (July 1, 2020-November 30, 2021). Primary outcomes were odds ratios (ORs) comparing top-box percentages of survey responses at multiple levels: individual questions, four domains, and all questions together as a composite. Key findings: Patients had higher odds of selecting top-box answers in the elective telehealth period for the Care Provider (1.09 [95% confidence interval 1.03, 1.16]) and General Assessment (1.13 [1.02, 1.24]) domains and the survey composite (1.08 [1.04, 1.13]), but there was no difference for individual questions. Women reported more positive experiences during the elective telehealth period in the Access (1.22 [1.01, 1.47]), Care Provider (1.32 [1.17, 1.50]), and Telemedicine Technology (1.24 [1.04, 1.50]) domains. Our findings suggest that patients had better telehealth experiences when mandates were relaxed.

Abstract Background The exponential growth of location-based social media (LBSM) data has ushered in novel prospects for investigating the urban food environment in health geography research. However, previous studies have primarily relied on word dictionaries with a limited number of food words and employed common-sense categorizations to determine the healthiness of those words. To enhance the analysis of the urban food environment using LBSM data, it is crucial to develop a more comprehensive list of food-related words. Within the context, this study delves into the exploration of expanding food-related words along with their associated energy densities. Methods This study addresses the aforementioned research gap by introducing a novel methodology for expanding the food-related word dictionary and predicting energy densities. Seed words are generated from official and crowdsourced food composition databases, and new food words are discovered by clustering food words within the word embedding space using the Gaussian mixture model. Machine learning models are employed to predict the energy density classifications of these food words based on their feature vectors. To ensure a thorough exploration of the prediction problem, ten widely used machine learning models are evaluated. Results The approach successfully expands the food-related word dictionary and accurately predicts food energy density (reaching 91.62%.). Through a comparison of the newly expanded dictionary with the initial seed words and an analysis of Yelp reviews in the city of Toronto, we observe significant improvements in identifying food words and gaining a deeper understanding of the food environment. Conclusions This study proposes a novel method to expand food-related vocabulary and predict the food energy density based on machine learning and word embedding. This method makes a valuable contribution to building a more comprehensive list of food words that can be used in geography and public health studies by mining geotagged social media data.

Introduction/Objective: Previous studies have evaluated the implementation of standardized social determinants of health (SDOH) screening within healthcare settings, however, less is known about where screening gaps may exist following initial implementation based on facility characteristics. The objective of this study is to assess differences in screening rates for SDOH at a large, urban healthcare system. Methods: We used electronic health record data obtained from NYC Health + Hospitals primary care sites from 2019 to 2022. We calculated the mean number of visits that were SDOH screened by visit type, facility size, and the percentages of community characteristics. We conducted 4 logistic regression models predicting the odds of screening for any SDOH and for specific SDOH needs (housing, food, and medical cost assistance) based on facility type, facility size, and the socioeconomic characteristics of the surrounding community. Results: Among the 3 212 650 visits included, 16.90% were SDOH screened. Across all 4 multivariate logistic regression models predicting SDOH screening, a visit had significantly lower odds of being screened if based at a midsize or small facility, if it was a telemedicine visit, or based at a facility located in a zip-code with a higher percentage of SDOH needs. Conclusions: Our study found important differences in SDOH screening rates at a large, NYC-based health system based on size, visit type, and community level characteristics. In particular, our findings point to barriers related to facility size and telemedicine workflow that should be addressed to increase uptake of SDOH screening within different visits and facility types.

Abstract Purpose To study the types of uveitis examined in a hospital serving indigent populations in need of low-cost care. Methods A retrospective chart review examined the electronic medical records of all patients with uveitis-related at Drexel Eye Physicians. Data collected included demographics, anatomic location of the uveitis, systemic disease associations, treatment modalities and insurance. Statistical analysis was performed using χ² or Fischer exact tests. Results 270 patients (366 eyes) were included for analysis, 67% of patients identified as African American. Most eyes (95.3%, N = 349) were treated with topical corticosteroid drops, and only 6 (1.6%) received an intravitreal implant. Immunosuppressive medications were started in 24 patients (8.9%). Nearly 80% depended to some extent on Medicare or Medicaid Assistance for treatment coverage. There was no association between insurance type and use of biologics or difluprednate. Conclusion We found no association between insurance type and the prescription of medications for uveitis that should be used at home. There was a minimal number of patients prescribed medications for implantation in the office. The adherence of use of medications at home should be investigated.

Ischemic stroke poses a significant global health challenge, necessitating ongoing exploration of its pathophysiology and treatment strategies. This comprehensive review integrates various aspects of ischemic stroke research, emphasizing crucial mechanisms, therapeutic approaches, and the role of clinical imaging in disease management. It discusses the multifaceted role of Netrin-1, highlighting its potential in promoting neurovascular repair and mitigating post-stroke neurological decline. It also examines the impact of blood–brain barrier permeability on stroke outcomes and explores alternative therapeutic targets such as statins and sphingosine-1-phosphate signaling. Neurocardiology investigations underscore the contribution of cardiac factors to post-stroke mortality, emphasizing the importance of understanding the brain–heart axis for targeted interventions. Additionally, the review advocates for early reperfusion and neuroprotective agents to counter-time-dependent excitotoxicity and inflammation, aiming to preserve tissue viability. Advanced imaging techniques, including DWI, PI, and MR angiography, are discussed for their role in evaluating ischemic penumbra evolution and guiding therapeutic decisions. By integrating molecular insights with imaging modalities, this interdisciplinary approach enhances our understanding of ischemic stroke and offers promising avenues for future research and clinical interventions to improve patient outcomes.

Pretreatment CT Perfusion (CTP) parameter rCBV < 42% lesion volume has recently been shown to predict 90-day mRS. In this study, we aim to assess the relationship between rCBV < 42% and a radiographic follow-up infarct volume delineated on FLAIR images. In this retrospective evaluation of our prospectively collected database, we included acute stroke patients triaged by multimodal CT imaging, including CT angiography and perfusion imaging, with confirmed anterior circulation large vessel occlusion between 9 January 2017 and 10 January 2023. Follow-up FLAIR imaging was used to determine the final infarct volume. Student t, Mann-Whitney-U, and Chi-Square tests were used to assess differences. Spearman’s rank correlation and linear regression analysis were used to assess associations between rCBV < 42% and follow-up infarct volume on FLAIR. In total, 158 patients (median age: 68 years, 52.5% female) met our inclusion criteria. rCBV < 42% (ρ = 0.56, p < 0.001) significantly correlated with follow-up-FLAIR infarct volume. On multivariable linear regression analysis, rCBV < 42% lesion volume (beta = 0.60, p < 0.001), ASPECTS (beta = −0.214, p < 0.01), mTICI (beta = −0.277, p < 0.001), and diabetes (beta = 0.16, p < 0.05) were independently associated with follow-up infarct volume. The rCBV < 42% lesion volume is independently associated with FLAIR follow-up infarct volume.

Abstract Circulating tumor DNA (ctDNA) sensitivity remains subpar for molecular residual disease (MRD) detection in bladder cancer patients. To remedy this problem, we focused on the biofluid most proximal to the disease, urine, and analyzed urine tumor DNA in 74 localized bladder cancer patients. We integrated ultra-low-pass whole genome sequencing (ULP-WGS) with urine cancer personalized profiling by deep sequencing (uCAPP-Seq) to achieve sensitive MRD detection and predict overall survival. Variant allele frequency, inferred tumor mutational burden, and copy number-derived tumor fraction levels in urine cell-free DNA (cfDNA) significantly predicted pathologic complete response status, far better than plasma ctDNA was able to. A random forest model incorporating these urine cfDNA-derived factors with leave-one-out cross-validation was 87% sensitive for predicting residual disease in reference to gold-standard surgical pathology. Both progression-free survival (HR = 3.00, p = 0.01) and overall survival (HR = 4.81, p = 0.009) were dramatically worse by Kaplan–Meier analysis for patients predicted by the model to have MRD, which was corroborated by Cox regression analysis. Additional survival analyses performed on muscle-invasive, neoadjuvant chemotherapy, and held-out validation subgroups corroborated these findings. In summary, we profiled urine samples from 74 patients with localized bladder cancer and used urine cfDNA multi-omics to detect MRD sensitively and predict survival accurately.

Abstract Background More than two years into the coronavirus disease (COVID-19) pandemic, it remains unclear whether financial incentives can reduce vaccine hesitancy and improve uptake among key unvaccinated populations. This study estimated the willingness of racial/ethnic minority adults in the United States to accept financial incentives for COVID-19 vaccination and the minimum amount needed to vaccinate a sufficiently high percentage of this population. Methods From August through September 2021, we conducted an online survey of 367 Black/African American and Hispanic patients, age ≥ 18 years, from 8 community health centers in Rhode Island. Contingent valuation questions assessed respondents’ willingness-to-accept (WTA) incentives for COVID-19 vaccination using random-starting-points and iterative incentive offers of $5 to $50 per dose. Ordered logistic regression models examined associations between respondent characteristics and WTA. Predictive probabilities were modeled using both within-survey range and out-of-survey range incentive offer amounts and compared against vaccination thresholds needed to reach herd immunity. Results Less than 30% of unvaccinated survey respondents were WTA an incentive of $50/dose for vaccination. Models using out-of-survey incentive offer amounts greater than $50 suggested that 85% of respondents would agree $140/dose (95% CI: $43-$236) could convince other people to accept vaccination, while $209/dose (95% CI: -$91-$509) would be needed for 85% of respondents to accept vaccination themselves. Conclusions Findings from this analysis may inform the design of incentive schemes aiming to reduce racial/ethnic disparities in vaccine and booster uptake, which will continue to be important as new variants of SARS-CoV-2 emerge.

Abstract Background Atrial myxomas account for approximately 50% of all primary cardiac tumors. The size, location, risk of embolic event, and involvement of other cardiac structures, are all factors that contribute to the wide range of presentation for cardiac myxomas. Patients with myxomas may remain asymptomatic, while others may report symptoms such as fatigue and fever, dyspnea, and syncope. It is important to recognize arrhythmias as an uncommon symptom of myxomas. Case presentation We report a rare case of a 67-year-old man who presented with pre-syncopal episodes, symptomatic bradycardia, and night sweats found to have a 5.5 × 5.1 × 3 cm myxoma in the left atrium. During diastole the mass caused dynamic flow obstruction across the mitral valve. The patient underwent surgical resection of the mass given his symptomatology and risk of embolic events. Removal of the myxoma resulted in resolution of both pre-syncopal episodes and the patient’s sinus bradycardia. Conclusion Atrial myxomas are a rare cause of pre-syncope and symptomatic bradycardia. It is important to have a clinical suspicion for atrial myxomas given early diagnosis and surgical intervention are key in improving the prognosis of these patients. This case also highlights the importance of taking into account the source of the myxoma’s blood supply in relationship to other cardiac structures, and further correlating these findings with clinical symptoms.

Pesticide overuse has resulted in serious ecological problems. Agricultural extension services play a key role in influencing farmers’ pesticide use. China has the world's largest public agricultural extension system, which has experienced a twisting path of reforms over the past four decades. However, there is little empirical evidence regarding the effects of agricultural extension services in the post-reform era since the mid-2000s. This study examines the effect of agricultural extension services in the post-reform era on pesticide use in China, using survey data of 1963 rice farmers in 2016 and 2018. Our results indicate that only 22.5% of surveyed farmers adopted agricultural extension services. After addressing the self-selectivity issue, the treatment effects model revealed that agricultural extension services in the post-reform era resulted in a 3.01 kg/ha reduction in total pesticide use, a 0.86 kg/ha reduction in application rate of active ingredients, and a 250 CNY/ha reduction in pesticide expenditure related to rice production. Our findings provide sound evidence that agricultural extension services in the post-reform era can result in a reduction in pesticide use for rice production. More effective efforts should be made to reinforce the provision of agricultural extension services and encourage farmers to adopt these services.

ABSTRACT Objective: To develop a well-detailed and reproducible tooth segmentation method, when quantifying tooth volumetric measurements is needed. Material and Methods: This was an in vitro study in which lower incisors and canines of five patients were 3D reconstructed by means of an automatic segmentation with manual refinements process. All the images were obtained using a 0.3-mm voxel size CBCT imaging. The software utilized was the ITK-SNAP®. The primary outcomes were the intra-rater and inter-rater reliabilities and the respective measurement errors. Results: The intra-rater reliability was excellent, with a mean measurement error of 4.16%. The inter-rater reliability was good, with a mean measurement error of 7.11%. Accuracy assessment was not possible, as the assessed teeth were not extracted. Conclusions: Although the described method is reliable, tooth volumetric error measurements may become significant, depending on the assessed situation.

Background: Cementless total knee arthroplasties (TKAs) have gained renewed interest due to improved implant designs and lower rates of revision than its cemented counterparts. The purpose of this study was to compare revision rates between cemented vs cementless TKAs within 1 year of primary arthroplasty. Methods: This was a retrospective review from the PearlDiver Patient Record Database. International Classification of Diseases and Current Procedural Terminology codes were used to identify patients who had undergone cemented and cementless TKAs and subsequent surgical revisions. An unadjusted univariate analysis of patient demographics, Charlson Comorbidity Index score, and surgical revisions at 90 days and 1 year after TKA was performed using chi-squared testing. Multivariate logistic regression analyses were subsequently performed for 1-year surgical complications requiring revision. Results: Of 324,508 patients, 312,988 (96.45%) underwent cemented TKAs, and 11,520 (3.55%) underwent cementless TKAs. Patients undergoing cementless TKA tended to be younger than patients undergoing cemented TKA (63.67 ± 9.15 cementless vs 66.22 ± 8.85 cemented, P < .001). Univariate chi-squared testing showed that cementless patients were more likely to require 1-component femoral or tibial revision at 90 days and 1 year, irrigation and debridement at 90 days and 1 year, and arthroscopy with lysis of adhesions at 1 year only. Similar findings were observed for these 3 revision procedures at 1 year after correcting for age, gender, and Charlson Comorbidity Index score using multivariate logistic regression analysis as cementless TKA patients had higher odds ratios for each of the revisions. Conclusions: Small but significant differences were found in surgical revisions among cementless TKAs when compared to cemented TKAs within 1 year of the index procedure.

Abstract In this paper, we construct Janus-type solutions of three-dimensional gauged supergravity with sixteen supersymmetries. We find solutions which correspond to interfaces between the same CFT on both sides, as well as RG-flow interfaces between CFTs with different numbers of supersymmetries and central charges. The solutions are obtained by solving the flow equations derived from the supersymmetry variations, and they preserve some fraction of the supersymmetries of the AdS3 vacua.

After cellular differentiation, nuclear DNA is no longer replicated, and many of the associated proteins are downregulated accordingly. These include the structure-specific endonucleases Fen1 and DNA2, which are implicated in repairing mitochondrial DNA (mtDNA). Two more such endonucleases, named MGME1 and ExoG, have been discovered in mitochondria. This category of nuclease is required for so-called “long-patch” (multinucleotide) base excision DNA repair (BER), which is necessary to process certain oxidative lesions, prompting the question of how differentiation affects the availability and use of these enzymes in mitochondria. In this study, we demonstrate that Fen1 and DNA2 are indeed strongly downregulated after differentiation of neuronal precursors (Cath.a-differentiated cells) or mouse myotubes, while the expression levels of MGME1 and ExoG showed minimal changes. The total flap excision activity in mitochondrial extracts of these cells was moderately decreased upon differentiation, with MGME1 as the predominant flap endonuclease and ExoG playing a lesser role. Unexpectedly, both differentiated cell types appeared to accumulate less oxidative or alkylation damage in mtDNA than did their proliferating progenitors. Finally, the overall rate of mtDNA repair was not significantly different between proliferating and differentiated cells. Taken together, these results indicate that neuronal cells maintain mtDNA repair upon differentiation, evidently relying on mitochondria-specific enzymes for long-patch BER.

There is a growing literature documenting the link between parental migration and children's health. However, few studies have explained the underlying mechanism of this observed relationship. This paper examines the effect of parental migration on children's health through dietary diversity, using survey data collected in a less developed prefecture in South Central China in 2018. To overcome the potential endogeneity of parental migration, we instrument parental migration with the proportion of households with migrated labor force at the village level, and find that parental migration reduces children's dietary diversity at home. Moreover, we provide suggestive evidence that the reduction in dietary diversity may attribute to significant negative separation effects whereas minimal positive income effects in migrant-sending households. This study highlights the negative effects of labor migration on the next generation's nutrition. In those developing countries with a high prevalence of labor migration, policies that facilitate access to dietary diversity of those left-behind children are warranted.

Global warming is caused by human activity, such as the burning of fossil fuels, which produces high levels of greenhouse gasses. As a consequence, climate change impacts all organisms and the greater ecosystem through changing conditions from weather patterns to the temperature, pH and salt concentrations found in waterways and soil. These environmental changes fundamentally alter many parameters of the living world, from the kinetics of chemical reactions and cellular signaling pathways to the accumulation of unforeseen chemicals in the environment, the appearance and dispersal of new diseases, and the availability of traditional foods. Some organisms adapt to extremes, while others cannot. This article asks five questions that prompt us to consider the foundational knowledge that biochemistry can bring to the table as we meet the challenge of climate change. We approach climate change from the molecular point of view, identifying how cells and organisms – from microbes to plants and animals – respond to changing environmental conditions. To embrace the concept of “one health” for all life on the planet, we argue that we must leverage biochemistry, cell biology, molecular biophysics and genetics to fully understand the impact of climate change on the living world and to bring positive change.

Research has shown mixed findings on the link between production diversity and household dietary diversity. The question is whether this link holds for children. In this study we examine the relationship between household's agricultural production diversity and child dietary diversity, and between production diversity and child nutritional status. Smallholder farm households (n = 1067) and children (n = 1067) aged 3-16 years from two then nationally designated poverty counties in Gansu Province of China were interviewed in 2019. Production diversity was assessed with the production richness score and production diversity score. Production diversity was calculated from agricultural production data covering a period of 12 months. Child dietary diversity was assessed with food variety score (FVS) and dietary diversity score (DDS). DDS was calculated based on 9 food groups using a 30-day recall method. Data were analysed using Poisson and Probit regression models. We find that both agricultural production richness score and revenue generated from selling agricultural products are positively associated with food variety score, with the relationship being stronger for the latter. Moreover, production diversity score is positively associated with children's dietary diversity score whereas negatively associated with their probability of being stunted, but not with their probabilities of being wasted or zinc deficient. Household social economics status were also positively associated with child dietary diversity.

In situ transcriptomics maps RNA expression patterns across intact tissues taking our understanding of gene expression to a new level. Here, the authors present a computational method that uncovers gene expression, cell niche, and tissue region patterns from 2D and 3D spatial transcriptomics.

**Introduction:** While the COVID-19 pandemic increased telehealth uptake, concerns surrounding access to telehealth visits emerged for older adults, especially those that are under-resourced, rural, and non-English speaking. We aimed to identify strategies employed by physicians to improve access to medical care via telehealth for older adults during the pandemic. **Methods:** Using purposeful sampling, we recruited physicians for 30-minute semi-structured interviews. The interviews focused mainly on telehealth’s usability for older patients, and specific strategies physicians employed to facilitate access to care for older adults with varied needs and skills. Interviews were coded using NVivo software and analyzed using framework matrix analysis. **Results:** Of 48 physicians (geriatrician n = 18, primary care n=15, emergency n=15) interviewed, median age was 37 (interquartile range 34-45), and 27 (56%) were women. Our data suggests that older adults who were under-resourced, rural, or non-English speaking faced greater challenges in using telehealth. Physicians addressed these barriers with strategies tailored to individual patient needs and practice setting resources. Strategies included employing auditory augmentation and speech modifications to enhance understanding, using caregivers and home services to overcome inexperience with navigating technology, device distribution programs for those without equipment access, and real-time interpreter technologies. Physicians reported that telehealth was successful in reducing transportation barriers, whether due to distance or mobility impairments, especially among older adult populations and reducing “no-show” appointment rates. **Conclusions:** Adoption of strategies to overcome technological and systemic barriers may improve equitable access to age-friendly telehealth for older adult patients. Physicians reported optimism that telehealth could be used to expand access to medical care for older adults with the right technological infrastructure, payment models, and support. Although challenges remain, they may be overcome with additional technical training for clinicians and patients, investment in telehealth infrastructure and broadband internet, and policy changes to promote telehealth access for this diverse patient population.

Over the past decade, Programmed Death-Ligand 1 (PD-L1) has emerged as a prominent target for cancer immunotherapies. However, its potential as an immunosuppressive therapy has been limited. In this review, we present the immunological basis of graft rejection and graft-versus-host disease (GVHD), followed by a summary of biologically relevant molecular interactions of both PD-L1 and Programmed Cell Death Protein 1 (PD-1). Finally, we present a translational perspective on how PD-L1 can interrupt alloreactive-driven processes to increase immune tolerance. Unlike most current therapies that block PD-L1 and/or its interaction with PD-1, this review focuses on how upregulation or reversed sequestration of this ligand may reduce autoimmunity, ameliorate GVHD, and enhance graft survival following organ transplant.

Abstract Janus solutions are constructed in d = 3, N $$ \mathcal{N} $$ = 8 gauged supergravity. We find explicit half-BPS solutions where two scalars in the SO(1, 8)/SO(8) coset have a nontrivial profile. These solutions correspond on the CFT side to an interface with a position-dependent expectation value for a relevant operator and a source which jumps across the interface for a marginal operator.

TRIUMF, Canada’s particle accelerator centre, is constructing a new high-power ISOL (Isotope Separation On-Line) facility called ARIEL (Advanced Rare IsotopE Laboratory). Thick porous targets will be bombarded with up to 48 kW of 480 MeV protons from TRIUMF’s cyclotron, or up to 100 kW of 30 MeV electrons from a new e-linac, to produce short-lived radioisotopes for a variety of applications, including nuclear astrophysics, fundamental nuclear structure and nuclear medicine. For efficient release of radioisotopes, the targets are heated to temperatures approaching 2000 °C, and are exposed to GSv/h level radiation fields resulting from intended fissions and spallations. Due to these conditions, the operational life for each target is only about five weeks, calling for frequent remote target exchanges to limit downtime. A few days after irradiation, the targets have a residual radiation field producing a dose rate on the order of 10 Sv/h at 1 m, requiring several years of decay prior to shipment to a national disposal facility. TRIUMF is installing new remote handling infrastructure dedicated to ARIEL, including hot cells and a remote handling crane. The system design applies learnings from multiple existing facilities, including CERN-ISOLDE, GANIL-SPIRAL II as well as TRIUMF’s ISAC (Isotope Separator and ACcelerator).

Abstract Background Left ventricular free wall rupture (LVFWR) is a rare complication after myocardial infarction and usually occurs 1 to 4 days after the infarct. Over the past decade, the overall incidence of LVFWR has decreased given the advancements in reperfusion therapies. However, during the COVID-19 pandemic, there has been a significant delay in hospital presentation of patients suffering myocardial infarctions, leading to a higher incidence of mechanical complications from myocardial infarctions such as LVFWR. Case presentation We present a case in which a patient suffered a LVFWR as a mechanical complication from myocardial infarction due to delay in seeking care over fear of contracting COVID-19 from the medical setting. The patient had been having chest pain for a few days but refused to seek medical care due to fear of contracting COVID-19 from within the medical setting. He eventually suffered a cardiac arrest at home from a massive inferior myocardial infarction and found to be in cardiac tamponade from a left ventricular perforation. He was emergently taken to the operating room to attempt to repair the rupture but he ultimately expired on the operating table. Conclusions The occurrence of LVFWR has been on a more significant rise over the course of the COVID-19 pandemic as patients delay seeking care over fear of contracting COVID-19 from within the medical setting. Clinicians should consider mechanical complications of MI when patients present as an out-of-hospital cardiac arrest, particularly during the COVID-19 pandemic, as delay in seeking care is often the exacerbating factor.

Objective: To investigate the influence of qigong on late positive potential, which was elicited by affective pictures. Methods: College students who met the inclusion criteria were enrolled and randomly allocated to the qigong group, which received a four-week training (n = 41) or the control group (n = 41). All participants were assessed before and after the training for event-related potential, which was elicited by negative, neutral, and positive pictures. Electrodes at the centerline position of the frontal area (FCz), parietal area (Pz), and occipital area (Oz) were analyzed. Results: Negative, neutral, and positive pictures demonstrated statistically significant differences on FCz (P

Objective: This study aimed to investigate the emotion regulation effect of Baduanjin Qigong on college students. Methods: The late positive potential (LPP) components were recorded while performing emotional pictures from 12 college students with Baduanjin Qigong experience and 12 with no experience of any mind–body exercises. Results: Under positive emotional stimuli, greater LPP amplitudes were observed in the experimental group in the frontal, central, and temporal areas than in the control group. Under negative emotional stimuli, greater LPP amplitudes were found in the experimental group in the prefrontal area and smaller amplitudes in the occipital area than in the control group. Conclusion: The results reveal the emotion regulation effect on the event-related potential of Baduanjin Qigong to college students. The findings suggest that the regulatory effect of Baduanjin Qigong on emotional stimulation may be a possible reason for reducing the symptoms of depression and anxiety.

OBJECTIVES: This report describes the extended follow-up (1941–2015) of a cohort of 38 549 automobile manufacturing workers with potential exposure to metalworking fluids (MWF). The outcomes of interest were mortality from cancers of the esophagus, stomach, intestine, rectum, bladder, liver, pancreas, larynx, lung, skin, prostate, brain, and female breast, as well as leukemia. This report includes 5472 deaths from cancer, more than ten times the numbers of deaths in our last summary report published 20 years ago. METHODS: Standardized mortality ratios were computed for the entire study period. Adjusted hazard ratios (HR) were estimated in Cox proportional hazard models with categorical variables for cumulative exposure to each type of MWF. RESULTS: Exposure–response patterns are consistent with prior mortality reports from this cohort. We found increased risk of skin and female breast cancer with straight fluids. For the first time, we found elevated risk of stomach cancer mortality. Overall, many of the exposure–response results did not suggest an association with MWF. CONCLUSIONS: Mortality is a poor proxy for cancer diagnosis for treatable cancers and not the optimal outcome measure in etiological studies. Although the HR presented here handle bias from the healthy worker hire effect and left truncation, they do not handle bias from healthy worker survivor effect, which likely results in underestimates of the health impacts of MWF. Although this updated summary provides some information on the risk of cancer from MWF, targeted future analyses will help clarify associations.

Abstract Background The human Obg-like ATPase 1 (OLA1) protein has been reported to play an important role in cancer cell proliferation. The molecular mechanism underlying OLA1 regulated oral metastasis is still unknown. We investigated in this study the regulatory role of OLA1 playing in oral squamous cell metastasis. Results A series of in vitro assays were performed in the cells with RNAi-mediated knockdown or overexpression to expound the regulatory function of OLA1 in oral cancer. We found that the endogenous level of OLA1 in a highly metastatic oral squamous cell line was significantly lower than that in low metastatic oral cells as well as in normal oral cells. Escalated expression of OLA1 resulted in a reduced ability of metastasis in highly metastatic cells, and enhanced its sensitivity to the paclitaxel treatment. Further analysis of the EMT markers showed that Snail, Slug, N-cadherin were up-expressed significantly. Meanwhile, E-cadherin was significantly down-regulated in the oral cancer cells with OLA1-knocked down, suggesting that OLA1 inactivated EMT process. Furthermore, we found that OLA1 suppressed oral squamous cell metastasis by suppressing the activity of a TGFβ/SMAD2/EMT pathway. Conclusion Our data suggests that OLA1 may be developed as a potential target for the treatment of oral cancer metastasis.

Telehealth services may improve access to care, but there are concerns around whether availability of telehealth may increase care utilization. We assessed whether usage of telehealth was associated with differential primary care utilization at a large, urban public healthcare system. Using electronic health record data from 23 primary care clinics, we categorized patients as telehealth users and non-users. Then, we compared the number of visits per patient between groups using Welch's t-tests while stratifying by comorbidity count. We used multivariable Poisson regression to test for associations between telehealth usage and visit count while controlling for other demographic factors. Compared with telehealth non-users, telehealth users had approximately 1 more primary care visit per patient over the year regardless of comorbidity count or other patient characteristics. Availability of telehealth services may be associated with increased primary care utilization in a safety-net setting, though further research on outcomes, costs of care, and patient and clinician experiences is needed to better inform decisions regarding provision and reimbursement of telehealth services.

Flare frequency distributions represent a key approach to addressing one of the largest problems in solar and stellar physics: determining the mechanism that counterintuitively heats coronae to temperatures that are orders of magnitude hotter than the corresponding photospheres. It is widely accepted that the magnetic field is responsible for the heating, but there are two competing mechanisms that could explain it: nanoflares or Alfvén waves. To date, neither can be directly observed. Nanoflares are, by definition, extremely small, but their aggregate energy release could represent a substantial heating mechanism, presuming they are sufficiently abundant. One way to test this presumption is via the flare frequency distribution, which describes how often flares of various energies occur. If the slope of the power law fitting the flare frequency distribution is above a critical threshold, α = 2 as established in prior literature, then there should be a sufficient abundance of nanoflares to explain coronal heating. We performed >600 case studies of solar flares, made possible by an unprecedented number of data analysts via three semesters of an undergraduate physics laboratory course. This allowed us to include two crucial, but nontrivial, analysis methods: preflare baseline subtraction and computation of the flare energy, which requires determining flare start and stop times. We aggregated the results of these analyses into a statistical study to determine that α = 1.63 ± 0.03. This is below the critical threshold, suggesting that Alfvén waves are an important driver of coronal heating.

A variety of genetic techniques have been devised to determine cell lineage relationships during tissue development. Some of these systems monitor cell lineages spatially and/or temporally without regard to gene expression by the cells, whereas others correlate gene expression with the lineage under study. The GAL4 Technique for Real-time and Clonal Expression (G-TRACE) system allows for rapid, fluorescent protein-based visualization of both current and past GAL4 expression patterns and is therefore amenable to genome-wide expression-based lineage screens. Here we describe the results from such a screen, performed by undergraduate students of the University of California, Los Angeles (UCLA) Undergraduate Research Consortium for Functional Genomics (URCFG) and high school summer scholars as part of a discovery-based education program. The results of the screen, which reveal novel expression-based lineage patterns within the brain, the imaginal disc epithelia, and the hematopoietic lymph gland, have been compiled into the G-TRACE Expression Database (GED), an online resource for use by the Drosophila research community. The impact of this discovery-based research experience on student learning gains was assessed independently and shown to be greater than that of similar programs conducted elsewhere. Furthermore, students participating in the URCFG showed considerably higher STEM retention rates than UCLA STEM students that did not participate in the URCFG, as well as STEM students nationwide.

Abstract Objectives Emergency medicine physicians have played a pivotal role throughout the coronavirus disease 19 (COVID‐19) pandemic through in‐person and remote management and treatment. Our primary objectives were to understand emergency medicine physicians’ experiences using telehealth throughout the pandemic, any facilitators/barriers to successful usage, lessons learned during implementation, and successful/abandoned strategies used to engage with older adults. Methods Using a semi‐structured interview guide, we conducted 30‐min interviews. We used purposeful sampling to recruit emergency medicine physicians from all United States regions, rural–urban settings, and academic and community practices, who reported caring for patients 65 years or older in‐person or virtually during the pandemic. Interviews were audio‐recorded, transcribed, double‐coded, and analyzed for emergent themes using framework analysis. Results A total of 15 in‐depth interviews were completed from September to November 2020. Physicians had a median age of 37 years, 7 were women, and 9 had experience with telehealth before the pandemic. We identified several themes: (1) there were various motivations for telehealth use; (2) telehealth was used primarily to supplement, not replace in‐person care; (3) most platforms were easy to use; (4) patients and caregivers had high acceptability of telemedicine; and (5) older adults with sensory and cognitive impairments often relied on caregivers. Emergency medicine physicians played a critical role during primary care office closures during the first wave—dispelling misinformation about COVID‐19, triaging patients to testing and treatment, and providing care that would otherwise have been deferred. Conclusions Our data show that telemedicine gained acceptability among emergency medicine physicians and provided options to patients who may have otherwise deferred care. These findings can inform future healthcare delivery for acute care needs or pandemic responses.

BackgroundThe standard of care treatment for muscle-invasive bladder cancer (MIBC) is radical cystectomy, which is typically preceded by neoadjuvant chemotherapy. However, the inability to assess minimal residual disease (MRD) noninvasively limits our ability to offer bladder-sparing treatment. Here, we sought to develop a liquid biopsy solution via urine tumor DNA (utDNA) analysis.Methods and findingsWe applied urine Cancer Personalized Profiling by Deep Sequencing (uCAPP-Seq), a targeted next-generation sequencing (NGS) method for detecting utDNA, to urine cell-free DNA (cfDNA) samples acquired between April 2019 and November 2020 on the day of curative-intent radical cystectomy from 42 patients with localized bladder cancer. The average age of patients was 69 years (range: 50 to 86), of whom 76% (32/42) were male, 64% (27/42) were smokers, and 76% (32/42) had a confirmed diagnosis of MIBC. Among MIBC patients, 59% (19/32) received neoadjuvant chemotherapy. utDNA variant calling was performed noninvasively without prior sequencing of tumor tissue. The overall utDNA level for each patient was represented by the non-silent mutation with the highest variant allele fraction after removing germline variants. Urine was similarly analyzed from 15 healthy adults. utDNA analysis revealed a median utDNA level of 0% in healthy adults and 2.4% in bladder cancer patients. When patients were classified as those who had residual disease detected in their surgical sample (n = 16) compared to those who achieved a pathologic complete response (pCR; n = 26), median utDNA levels were 4.3% vs. 0%, respectively (p = 0.002). Using an optimal utDNA threshold to define MRD detection, positive utDNA MRD detection was highly correlated with the absence of pCR (p < 0.001) with a sensitivity of 81% and specificity of 81%. Leave-one-out cross-validation applied to the prediction of pathologic response based on utDNA MRD detection in our cohort yielded a highly significant accuracy of 81% (p = 0.007). Moreover, utDNA MRD-positive patients exhibited significantly worse progression-free survival (PFS; HR = 7.4; 95% CI: 1.4-38.9; p = 0.02) compared to utDNA MRD-negative patients. Concordance between urine- and tumor-derived mutations, determined in 5 MIBC patients, was 85%. Tumor mutational burden (TMB) in utDNA MRD-positive patients was inferred from the number of non-silent mutations detected in urine cfDNA by applying a linear relationship derived from The Cancer Genome Atlas (TCGA) whole exome sequencing of 409 MIBC tumors. We suggest that about 58% of these patients with high inferred TMB might have been candidates for treatment with early immune checkpoint blockade. Study limitations included an analysis restricted only to single-nucleotide variants (SNVs), survival differences diminished by surgery, and a low number of DNA damage response (DRR) mutations detected after neoadjuvant chemotherapy at the MRD time point.ConclusionsutDNA MRD detection prior to curative-intent radical cystectomy for bladder cancer correlated significantly with pathologic response, which may help select patients for bladder-sparing treatment. utDNA MRD detection also correlated significantly with PFS. Furthermore, utDNA can be used to noninvasively infer TMB, which could facilitate personalized immunotherapy for bladder cancer in the future.

Although virtually all gene networks are predicted to be controlled by miRNAs, the contribution of this important layer of gene regulation to tissue homeostasis in adult animals remains unclear. Gain and loss-of-function experiments have provided key insights into the specific function of individual miRNAs, but effective genetic tools to study the functional consequences of global inhibition of miRNA activity in vivo are lacking. Here we report the generation and characterization of a genetically engineered mouse strain in which miRNA-mediated gene repression can be reversibly inhibited without affecting miRNA biogenesis or abundance. We demonstrate the usefulness of this strategy by investigating the consequences of acute inhibition of miRNA function in adult animals. We find that different tissues and organs respond differently to global loss of miRNA function. While miRNA-mediated gene repression is essential for the homeostasis of the heart and the skeletal muscle, it is largely dispensable in the majority of other organs. Even in tissues where it is not required for homeostasis, such as the intestine and hematopoietic system, miRNA activity can become essential during regeneration following acute injury. These data support a model where many metazoan tissues primarily rely on miRNA function to respond to potentially pathogenic events.

Superficial fungal diseases of the skin and nails are an increasingly common occurrence globally, requiring effective topical treatment to avoid systemic adverse effects. Polymeric nanoparticles have demonstrated sustained and effective drug delivery in a variety of topical formulations. The aim of this project was to develop polymeric antifungal nanospheres containing terbinafine hydrochloride (TBH) to be loaded into a hydrogel formulation for topical nail drug delivery. A quality by design (QbD) approach was used to achieve optimized particles with the desired quality target product profile (QTPP). Polyvinyl alcohol (PVA) at 2% w/v and a drug to polymer ratio of 1:4, together with a robust set of processes and material attributes, resulted in nanoparticles of 108.7 nm with a polydispersity index (PDI) of 0.63, 57.43% recovery, and other desirable characteristics such as zeta potential (ZP), particle shape, aggregation, etc. The nanospheres were incorporated into a carbomer-based gel, and the delivery of TBH through this formulation was evaluated by means of in vitro drug release testing (IVRT) and ex vivo nail permeation study. The gel containing the TBH nanospheres demonstrated a slower and controlled drug release profile compared with the control gel, in addition to a more efficient delivery into the nail. These antifungal nanospheres can be utilized for topical therapy of a multitude of superficial fungal infections.

The fungal disease of the nail, onychomycosis, which is also the most prevalent nail disturbance, demands effective topical treatment options considering the possible adverse effects of systemic antifungal therapy. The current work is focused on development of an adhesive and resistant, drug-delivering and permeation-enhancing polymeric film containing econazole nitrate (ECN) for topical antifungal treatment. The development of the lacquer formulation was guided by the Quality by Design approach to achieve the critical quality attributes needed to obtain the product of desired quality. Eudragit RSPO at 10% w/w was found to be the ideal adhesive polymer for the application and an optimal permeation-enhancing lacquer formulation was achieved by the optimization of other formulation excipients, such as plasticizer and the solvent system. Additionally, novel experimental enhancements introduced to the research included refined D50 drying time and drying rate tests for lacquer characterization as well as a multi-mechanism permeation-enhancing pre-treatment. Moreover, a practical implication was provided by a handwashing simulation designed to test the performance of the lacquer during actual use. In vitro drug release testing and ex vivo nail permeation testing demonstrated that the optimized nail lacquer performed better than control lacquer lacking the permeation enhancer by achieving a faster and sustained delivery of ECN. It can be concluded that this is a promising drug delivery system for topical antifungal treatment of onychomycotic nails, and the novel characterization techniques may be adapted for similar formulations in the future.