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The introduction of effective human papillomavirus (HPV) vaccination, screening, and treatment programs has led the World Health Organization to call for the global elimination of cervical cancer. Assessing progress toward this goal is supported through monitoring vaccination coverage and its impact. We performed a targeted review to assess the characteristics of HPV-related data systems from seven high-income countries (HICs) that represented varied approaches, including Australia, Canada, France, Italy, Scotland, Sweden, and the United States (US). Included data systems focused on preventive and early detection measures: HPV vaccination and cervical screening programs, as well as HPV-related disease outcomes. Differences were observed in approach to development of data systems, along with variation in geographical scope and methods of data collection. A challenge exists in how to best follow-up the ongoing global-scale elimination efforts in a comprehensive manner. These sources provide a wealth of information regarding the strengths and limitations of, and notable variation among, current data systems used in HICs. This review can inform improvements to existing prevention programs and the implementation of new programs in other countries, and thus support optimization of cervical cancer prevention policy.

Aim: Whole-genome methylation sequencing carries both DNA methylation and structural variant information (single nucleotide variant [SNV]; copy number variant [CNV]); however, limited data is available on the reliability of obtaining this information simultaneously from low-input DNA using various library preparation and sequencing protocols. Methods: A HapMap NA12878 sample was sequenced with three protocols (EM-sequencing, QIA-sequencing and Swift-sequencing) and their performance was compared on CpG methylation measurement and SNV and CNV detection. Results: At low DNA input (10–25 ng), EM-sequencing was superior in almost all metrics except CNV detection where all protocols were similar. EM-sequencing captured the highest number of CpGs and true SNVs. Conclusion: EM-sequencing is suitable to detect methylation, SNVs and CNVs from single sequencing with low-input DNA.

Children exposed to parental opioid use disorder are at an elevated risk of maltreatment. We study whether parents’ access to medication-assisted opioid treatment programs (OTPs) affects the well-being of their children. An administrative decision to lift a moratorium on access to these programs in Indiana created the opportunity for this study. We show that after a county opened an OTP, methadone dispensing increased and emergency department visits related to opioid overdose decreased there, offering evidence of the success of these programs. We also show that the opening of these OTPs did not have significant effects on reports of child maltreatment, but that out-of-home foster care placements were reduced by 22 percent. Our findings are consistent with past research showing that child welfare cases involving parental substance use tend to be complex and tend to have longer times to parent/child reunification than child welfare cases in which substance use is not present. We argue that expanding access to opioid treatment programs may help reduce foster care placements.

Miniaturized, multicolored light-emitting device arrays are promising for applications in sensing, imaging, computing, and more, but the range of emission colors achievable by a conventional light-emitting diode is limited by material or device constraints. In this work, we demonstrate a highly multicolored light-emitting array with 49 different, individually addressable colors on a single chip. The array consists of pulsed-driven metal-oxide-semiconductor capacitors, which generate electroluminescence from microdispensed materials spanning a diverse range of colors and spectral shapes, enabling facile generation of arbitrary light spectra across a broad wavelength range (400 to 1400 nm). When combined with compressive reconstruction algorithms, these arrays can be used to perform spectroscopic measurements in a compact manner without diffractive optics. As an example, we demonstrate microscale spectral imaging of samples using a multiplexed electroluminescent array in conjunction with a monochrome camera.

Purpose:BRAFV600E mutations are associated with poor clinical prognosis in colorectal cancer (CRC). Although selective BRAF inhibitors are effective for treatment of melanoma, comparable efforts in CRC have been disappointing. Here, we investigated potential mechanisms underlying this resistance to BRAF inhibitors in BRAFV600E CRC.Experimental Design: We examined phosphoinositide 3-kinase (PI3K)/mTOR signaling in BRAFV600E CRC cell lines after BRAF inhibition and cell viability and apoptosis after combined BRAF and PI3K/mTOR inhibition. We assessed the efficacy of in vivo combination treatment using a novel genetically engineered mouse model (GEMM) for BRAFV600E CRC.Results: Western blot analysis revealed sustained PI3K/mTOR signaling upon BRAF inhibition. Our BRAFV600E GEMM presented with sessile serrated adenomas/polyps, as seen in humans. Combination treatment in vivo resulted in induction of apoptosis and tumor regression.Conclusions: We have established a novel GEMM to interrogate BRAFV600E CRC biology and identify more efficacious treatment strategies. Combination BRAF and PI3K/mTOR inhibitor treatment should be explored in clinical trials. Clin Cancer Res; 19(10); 2688–98. ©2013 AACR.

Supplementary Figure 1 PDF file 118K, Development a GEMM for BRAFV600E CRC

Supplementary Figure 2 PDF file 152K, APC tumors do not recapitulate the sessile serrated CRC pathway

Supplementary Figure Legends PDF file 89K, Supplementary Figure Legends for Supplementary Figure 1 and Supplementary Figure 2

Congenital cytomegalovirus infection (cCMVi) is the leading cause of nonhereditary sensorineural hearing loss and can cause other long-term neurodevelopmental disabilities; however, data on the economic burden of cCMVi during early childhood are scarce. The primary objective of the study was to describe longitudinal patterns of health care resource utilization (HCRU) and direct medical costs among infants with cCMVi compared to infants unexposed to cCMVi.A retrospective cohort study was performed using data on infants born between 2013 and 2017, as captured in the database of Maccabi Healthcare Services, a 2.5 million-member health care organization in Israel. cCMVi cases were identified by physician diagnosis and/or dispensed valganciclovir within 90 days after birth. Infants born to mothers CMV-seronegative throughout pregnancy were selected for comparison (unexposed controls). Infants were retrospectively followed up through December 31, 2018, or 4 years of age (Y4). HCRU included physician visits, hospital admissions, audiology tests/procedures, imaging, and valganciclovir treatment. Direct medical costs, in US dollars per person per year (USD PPPY) were calculated from the health-system perspective. To compare costs of cCMVi cases and controls, direct medical costs were estimated using a generalized linear model with a log link function and γ distribution after adjustment for patient characteristics.A total of 351 cCMVi cases and 11,733 control infants with continuous follow-up during their first year of life (Y1) were included in the study. In Y1, cases were more likely to have a hospital admission (8.5% cases vs 4.5% control; P0.001) and higher numbers of pediatrician visits (median, 18 vs 15), audiology visits and tests, and cranial ultrasounds (all, P0.05). Longitudinally, incremental costs associated with cases were highest in Y1 (1686.7 USD PPPY; cost ratio = 2.6; P0.001) and remained elevated through Y4.cCMVi was associated with substantial increases in HCRU and economic burden during early childhood, and particularly during the first year of life.

Introduction: Latinx and Asian American communities in the U.S. face unique yet similar structural barriers to maintaining adequate diet quality, contributing to an increased burden of diabetes and non-alcoholic fatty liver disease in these groups. These inequities have been exacerbated in recent years due to overt anti-immigrant and anti-Asian sentiment during the COVID-19 pandemic, invoking fear and cultural shame for these groups, and amplifying challenges towards accessing food and economic stability. Hypothesis: Herein we describe a community-centered, multi-level approach aligned with the National Institute of Minority Health and Health Disparities Framework. We hypothesize our study will result in increased fruit and vegetable intake (self-report, measured via skin carotenoids), social cohesion and ethnic pride at the individual level and improved socioeconomic outcomes at the neighborhood level. Methods: Working collaboratively with 8 community-based and farm partners, the goal of the Building Access to Food through Systems and Solidarity (BASIS) Study is to improve diet and economic stability in Sunset Park—a neighborhood of Mexican and Chinese American families in Brooklyn, NY. This neighborhood has been hard-hit during the COVID-19 pandemic and lagged in economic recovery, and its residents are disconnected from government support. BASIS addresses food access, nutrition education, policy change, and hands-on learning (e.g., gardening, cooking) incorporating culturally appropriate values, foods, and taste preferences throughout each of these activities. Results: To date, we have held four group model-building workshops with partners to identify common priorities/goals towards improving nutrition in immigrant communities; co-developed Mexican and Chinese American-specific nutrition education materials; held eight virtual and in-person sessions with community members (n=291); conducted qualitative interviews (n=19) and quantitative data collection (n=175) amongst community residents to inform program development; and implemented a subsidized, community-supported agriculture pilot program for 20 weeks in 2022 (n=38). BASIS resources have been well-received by community members, with high engagement (90% attend weekly produce box pick-up events) and acceptance (100% indicated they would recommend the program to others). Conclusions: Planned evaluation will include mixed methods and administrative data analyses for assessment of multi-level outcomes. BASIS will expand to more participants (n=150), and will include additional program components (e.g., food policy assessment; workforce development; small business owner education). BASIS presents a powerful model to improve diet in immigrant communities applying systems thinking and community-centered best practices, lessons which may be gleaned for other immigrant communities.

Background In the U.S., HIV transmission persists largely through sexual transmission in gender and sexual minorities. Transactional sex (TS) is a known risk factor for HIV transmission, yet risk behaviors and engagement in HIV treatment and other medical services among transgender (TG) individuals who have TS are poorly understood. Methods PATCH is a natural history study of TG individuals in Washington, DC. Participants complete laboratory testing and surveys, including assessment of TS – defined as previous year sex in exchange for drugs, money or shelter. Fisher’s exact test was used for statistical analysis. Results Of 54 participants assigned male at birth (AMAB), 21(39%) endorsed TS, the majority of whom were female (81%), Black (95%), median age 35, and HIV+ (76%; Table 1). Of those with HIV, 12 (75%) were prescribed ART, though only 8 (50%) had HIV VL < 200. The majority of TG people with TS had sex weekly or more (75%), with > 5 partners/year (62%) and used their penis (80%) and anus (90%) during TS. A minority consistently used condoms in receptive anal sex (29%), penetrative anal sex (25%), penetrative vaginal sex (17%), and chem sex (8%). While 95% had ever taken gender affirming hormone therapy (GAHT), 62% were not prescribed GAHT at screening, of whom, 54% were interested in seeing a provider for GAHT. When compared to non-TS participants, TG individuals with TS were more likely to have chem sex (p< 0.01), use drugs daily or more (p=0.04), use amphetamines (p< 0.01) and cocaine (p< 0.01), and less likely to have GAHT prescribed by a provider (p=0.03). HIV+ patients with TS were less likely to have HIV VL< 200 (p=0.02). Table 1:Participant Characteristics and Associations with Transactional Sex Conclusion This cohort of AMAB TG individuals with TS had high rates of viremic HIV, and multiple risk factors for HIV transmission, including frequent condomless sex with multiple partners. Additionally, those with TS were more likely to have high risk drug use, indicating that novel strategies to decrease risk associated with chem sex, particularly stimulant use, should be prioritized. Further, nearly all TG participants with TS had taken GAHT, yet were less likely to get GAHT from a provider. As many had interest in seeing a provider for GAHT, co-locating GAHT with HIV treatment and prevention services could help providers engage this population and address HIV-related risks. Disclosures Shyam Kottilil, MD, PhD, Arbutus Pharmaceuticals: Grant/Research Support|Gilead: Grant/Research Support|Merck: Grant/Research Support|Regeneron Pharmaceuticals: Advisor/Consultant|Silverback Therapeutics: Advisor/Consultant|The Liver Company: Advisor/Consultant|Yufan Biotechnologies: Advisor/Consultant Sarah Kattakuzhy, MD, Gilead: Grant/Research Support Elana S. Rosenthal, MD, Gilead: Grant/Research Support|Merck: Grant/Research Support.

Background In the United States, HIV is highly prevalent among transgender individuals, but factors contributing to viremia in this population are poorly understood. We aimed to assess factors associated with HIV viremia among transgender people living with HIV (PLWH). Methods PATCH is a longitudinal natural history study of transgender individuals in Washington, DC. Participants complete laboratory assessments, as well as surveys assessing demographics, behaviors, and mental health. Patients whose HIV viral load was >200 copies/mL at screening were considered viremic. Fisher’s exact test was used for statistical analysis. Results Of 62 enrolled participants, 35(56%) were HIV+, the majority of whom were prescribed antiretroviral therapy (31, 89%) and had an undetectable viral load (25, 71%). Of PLWH, 35(100%) were assigned male at birth, 34(97%) were Black, and the median age was 37 years. PLWH were predominately stably housed (24, 69%), with 9(26%) reporting daily drug use or more, and 16(46%) reporting transactional sex within a year. When comparing PLWH who were viremic versus those virally suppressed, viremic PLWH were less likely to be prescribed antiretroviral therapy (60% vs 100%, p=0.004), and more likely to have unstable housing (60% vs 25%, p=0.04), use drugs daily or more in the last month (60% vs 12%, p=0.007), and engage in transactional sex in the last 12 months (80% vs 32%, p=0.02). HIV viral suppression was not significantly associated with number of sexual partners within the last 12 months or always using condoms during any type of sex (p >0.05). Conclusion In this cohort of transgender PLWH, we found moderate rates of HIV viremia associated with chaotic life factors such as daily drug use, unstable housing, and engaging in transactional sex. In addition, we found low rates of consistent condom use despite multiple sexual partners, regardless of viral load. Comprehensive care programs that improve access to ART, address substance use disorders and facilitate housing may serve to improve treatment outcomes and reduce risk of HIV transmission in this population. Disclosures Shyam Kottilil, MD, PhD, Arbutus Pharmaceuticals: Grant/Research Support|Gilead: Grant/Research Support|Merck: Grant/Research Support|Regeneron Pharmaceuticals: Advisor/Consultant|Silverback Therapeutics: Advisor/Consultant|The Liver Company: Advisor/Consultant|Yufan Biotechnologies: Advisor/Consultant Elana S. Rosenthal, MD, Gilead Sciences: Grant/Research Support|Merck: Grant/Research Support.

Endothelial cells (ECs) can present antigens to circulating effector memory T cells (TEM) and to regulatory T cells (T regs), triggering antigen-specific extravasation at specific sites where foreign antigens are introduced, e.g. by infection or transplantation. We model human antigen-induced transendothelial migration (TEM) using presentation of superantigen by cultured human dermal microvascular (HDM)ECs to isolated resting human peripheral blood T cell subpopulations or to T effector cells activatedin vitro. T cell receptor (TCR)-mediated cytokine synthesis, a common assay of T cell activation by antigen, is modulated by antigen-independent signals provided by various positive or negative costimulator proteins (the latter known as checkpoint inhibitors) expressed by antigen presenting cells, including ECs. We report here that some EC-expressed costimulators also modulate TCR-TEM, but effects differ between TEM and cytokine production and among some T cell types. Blocking EC LFA-3 interactions with TEMCD2 boosts TEM but reduces cytokine production. Blocking EC ICOS-L interactions with TEMCD28 (but not ICOS) reduces both responses but these involve distinct CD28-induced signals. Activated CD4+ T effector cells no longer undergo TCR-TEM. Engagement of T cell CD28 by EC ICOS-L increases TCR-TEM by activated CD8 effectors while engagement of OX40 promotes TCR-TEM by activated CD4 T regs. B7-H3 mostly affects TEM of resting TEMand some checkpoint inhibitors affect cytokine synthesis or TEM depending upon subtype. Our data suggest that blockade or mimicry of costimulators/checkpoint inhibitorsin vivo, clinically used to modulate immune responses, may act in part by modulating T cell homing.

Digital art has become a part of daily life. Despite the rising popularity of digital art and its advantages over traditional art, it is still unclear what the impact digital art has on the job market for artists today. This research provided a practical and quantitative method to investigate the impact of the rising popularity of digital art on the national job market for artists today. This study collected and sampled online data across the US and performed quantitative analysis. This study shows, in the study period (January-April, 2021), around 22,500 artist jobs available, and over 1% (2400) of them are high-paid jobs with an annual salary of over 100 K, and over 3% (7515) of them are medium-paid jobs with a salary of over 65 K. The majority (66%) of artist jobs with an annual salary of over 60 K are related to digital art and come from technology sectors. The digital art jobs are across the nation, not clustered around major cities.

Objective Atopic dermatitis (AD) is a chronic inflammatory skin disease that is complicated by an increased risk for skin and systemic infections. Preventive therapy for AD is based on skin barrier improvement and anti-inflammatory treatments, whereas overt skin and systemic infections require antibiotics or antiviral treatments. This review updates the pathophysiology, diagnosis, management, controversy of antibiotic use, and potential treatments of infectious complications of AD. Data Sources Published literature obtained through PubMed database searches and clinical pictures. Study Selections Studies relevant to the mechanisms, diagnosis, management, and potential therapy of infectious complications of AD. Results Skin barrier defects, type 2 inflammation, Staphylococcus aureus colonization, and cutaneous dysbiosis are the major predisposing factors for the increased infections in AD. Although overt infections require antibiotics, the use of antibiotics in AD exacerbation remains controversial. Conclusion Infectious complications are a comorbidity of AD. Although not common, systemic bacterial infections and eczema herpeticum can be life-threatening. Preventive therapy of infections in AD emphasizes skin barrier improvement and anti-inflammatory therapy. The use of antibiotics in AD exacerbation requires further studies.

Within the recent modernization of pharmaceutical manufacturing, an important milestone consists in developing enabling technologies for end-to-end continuous production of drug products. Continuous filtration, washing and drying of active pharmaceutical ingredients from mother liquors in upstream manufacturing are critical steps for achieving end-to-end continuous production. In this work, we develop a mathematical model for a novel intensified carousel system capable of continuously filtering, washing and drying a slurry stream into a dry crystals cake. The mathematical model consists of detailed dynamic differential mass, energy and momentum balances, capable of tracking the solvents and impurities content in the cake (critical quality attributes) across the entire carousel. We successfully demonstrate the model features by identifying the probabilistic design space in a simulation study for the isolation of aspirin crystals in the carousel, accounting for model uncertainty through Monte Carlo simulations.

Summary Optical communication and interconnects utilize high-speed light sources for information transmission. The modulation frequency of light-emitting devices operating through spontaneous emission is fundamentally limited by the material intrinsic radiative lifetime. In this perspective, we examine the radiative lifetime of different materials and identify the superradiant molecular J aggregates as a promising class of materials for high-speed light-emitting devices. These molecular aggregates are relatively unexplored for electroluminescent devices and can have short radiative lifetime on the order of 10 ps while maintaining high photoluminescence quantum yield. The relation between intermolecular interactions, molecular packing geometry, and radiative lifetimes is presented theoretically in the context of Frenkel excitons and is corroborated with experimental examples. We further demonstrate the potential of designing superradiant materials through molecular engineering. We believe that these superradiant molecular materials will open up new opportunities in the fabrication of efficient and high-speed light-emitting devices.

The range of luminescent materials that can be used in electroluminescent devices is limited due to material processing challenges and band alignment issues. This impedes the development of electroluminescent devices at extreme wavelengths and hinders the use of electroluminescence spectroscopy as an analytical technique. Here, we show that a two-terminal device that uses an array of carbon nanotubes as the source contact can excite electroluminescence from various materials independent of their chemical composition. Transient band bending, created by applying an a.c. gate voltage, is used to achieve charge injection across different band alignments. As a result, the device can produce electroluminescence from long-wave infrared (0.13 eV) to ultraviolet (3.3 eV) wavelengths depending on the emitting material drop-casted on top of the nanotube array, and with onset voltages approaching the optical energy gap of the emitting material. We show that our device can be used to probe a chemical reaction in a liquid droplet via electroluminescence spectroscopy and can be used as an electroluminescence sensor for detecting organic vapours. A two-terminal device that uses an array of carbon nanotubes as the source contact can excite electroluminescence from a variety of materials, producing electroluminescence from long-wave infrared to ultraviolet wavelengths, with onset voltages approaching the optical energy gap of the emitting material.

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Purpose: To determine the evolution of abdominal aortic aneurysm (AAA) diameter in the presence of persisting type 2 endoleaks (pEL2) following endovascular abdominal aortic aneurysm repair (EVAR). Materials and Methods: This is a retrospective, single-center, case-control study. All patients with pEL2 (pEL2 group, persisting for > 12 months) between 2004 and 2018 were identified and compared with a 1:1 age- and gender-matched control with no endoleak (control group). Primary outcome measures were freedom from AAA expansion and freedom from AAA shrinkage over time. AAA diameter measurements were performed on computed tomography angiography (CTA). Secondary outcome measures were survival, AAA-related mortality, reinterventions for pEL2, incidence of secondary type 1 endoleaks (EL1), and infrarenal aortic branch vessel anatomy. Results: A total of 773 patients were treated with EVAR for AAA between 2004 and 2018. Of them, 286 patients demonstrated type 2 endoleaks (EL2) in postoperative CTA or intraoperative angiography (37%). Forty-five of 286 EL2 (15.7%) were pEL2 (pEL2 group). Freedom from AAA expansion in the pEL2 group was 100%, 96.7%, 85.2%, and 54.3% after 1, 2, 3, and 4 years, respectively, compared with 100% after 1, 2, 3, and 4 years in the control group (pConclusion: pEL2 are associated with AAA expansion during midterm FU. Further studies are warranted to evaluate the association of AAA expansion due to pEL2 with clinical outcomes to allow recommendations with regard to treatment indications.

Pleural mesothelioma (PM) comprises three major histologic types: epithelioid, sarcomatoid, and a mixture of the two types termed biphasic. We and others have investigated whole transcriptome profiles of bulk PM samples, identifying a molecular gradient with features of epithelial-mesenchymal transition, which is related to, but not redundant with, histology. To date bulk studies of heterogeneity across PM tumors have not explained how biphasic tumors contain sarcomatoid (mesenchymal) and epithelioid (epithelial) components. We hypothesized that sarcomatoid and epithelioid components arose from distinct tumor clones. We performed integrated bulk and single-cell RNA-sequencing and pathologic analyses of 93 samples from 39 patients’ surgical resections including 3 negative-control pleura cases with non-PM pathology. Single-cell sequencing analysis was performed using the Seq-Well S3 platform. Tumor clones were identified using inferCNV in R. Copy number and somatic variants were identified in adjacent bulk samples of each PM case with optical genome mapping and exome sequencing, respectively. We generated libraries from 19 epithelioid, 3 sarcomatoid, and 13 biphasic cases resulting in an average of 6,657 single cells per case (n=266,262 total cells; UMIs ≥ 300 & features ≥ 80). Among the 32,383 high quality malignant cells, we characterized epithelioid and sarcomatoid programs independent of non-malignant cells in the microenvironment. We observed malignant cells expressing both programs at low levels, termed uncommitted. Uncommitted cells were not outliers in terms of UMIs detected, genes expressed, or mitochondrial transcript content, and were detected in 96.4% of PM cases with at least 50 high quality tumor cells. Most (72.7%) uncommitted cells were isolated from biphasic tumors. Additionally, we observed that individual tumor clones from biphasic tumors exhibited all three cell phenotypes. In one biphasic tumor, five of six clones comprised cells from all three types, where these clones were well-represented across multiple sites with epithelioid content ranging from 10% to 40%. In conclusion, our integrated analysis of multi-site pleural mesothelioma samples suggests that a single tumor clone may be capable of generating all molecular subtypes. Further work aims to identify candidate drivers of this plasticity, to relate single-cell transcriptomic phenotype to histology and to further characterize uncommitted cells. We will also assess the prognostic implications of uncommitted cells content in a wider cohort. Citation Format: David T. Severson, Samuel Freyaldenhoven, Benjamin Wadowski, Travis Hughes, Yin P. Hung, Roderick V. Jensen, William G. Richards, Corinne E. Gustafson, Kimberly Vermilya, Simona Innocenti, Julianne S. Barlow, Matthew B. Cougar, Jamie Anderson, Vivian Wang, Mary N. Dao, Alex K. Shalek, Assunta De Rienzo, Raphael Bueno. Uncommitted cells and phenotypic plasticity elucidate the complexity of the epithelial-mesenchymal molecular gradient of pleural mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 95.

Coronavirus-19 misinformation poses a unique challenge for public health communication efforts. In rural communities, COVID-19 misinformation is not well studied. We investigate patients' ability to discriminate COVID-19 fact from fiction from their news sources, as well as general COVID-19 knowledge, perceptions, public health practices, and their primary news sources in 258 adult patients at a primary health clinic in rural Michigan. Most of the population surveyed was able to correctly differentiate reliable COVID-19 public health information from fabricated information. However, only 55.4% of participants reported that they would be somewhat or extremely likely to get a COVID-19 vaccine. The most reported news source was mainstream broadcast television channels such as CBS and ABC. Our data support those older participants are better informed and more likely to practice safe public health practices than younger participants. Based on our data, we offer strategies for public health campaigns in rural communities, such as targeted interventions towards younger people and utilizing local television stations and community institutions to disseminate public health communications and health promotions. Public health interventions beyond education should be considered to mitigate the gap between COVID-19 knowledge and prevention behaviors. Future studies should investigate the role of health care providers in COVID-19 communication with patients, understanding hesitations toward COVID-19 vaccination, and communication strategies to best increase COVID-19 vaccine uptake in rural communities.

Human papillomavirus (HPV) infection, which poses significant disease burden, is decreasing following implementation of vaccination programs. Synthesized evidence on HPV vaccine real-world benefit was published in 2016. However, long-term impact of vaccination, and how vaccination programs influence infection rates and disease outcomes, requires further examination. We systematically reviewed observational studies on HPV vaccination within MEDLINE, EMBASE, and Google Scholar from 2016 to 2020, involving 14 years of follow-up data. We identified 138 peer-reviewed publications reporting HPV vaccine impact or effectiveness. Outcomes of interest included rates of infection at different anatomical sites and incidence of several HPV-related disease endpoints. The expansion of HPV vaccination programs worldwide has led to a reduction in genital infection and significant decreases in incidence of HPV-related disease outcomes. Therefore, the WHO has set goals for the elimination of cervical cancer as a public health concern. To track progress toward this requires an understanding of the effectiveness of different vaccination initiatives. However, the impact on males, and potential benefit of gender-neutral vaccination programs have not been fully explored. To present an accurate commentary on the current outlook of vaccination and to help shape policy therefore requires a systematic review of available data.

Congenital cytomegalovirus infection (cCMVi) is the leading cause of nonhereditary sensorineural hearing loss among newborns. Women newly acquiring cytomegalovirus infection (CMVi) during pregnancy have the highest risk of vertical transmission. This study aimed to describe the epidemiology of CMVi in pregnancy in a large healthcare database. A retrospective cohort study was performed using the Maccabi Healthcare Services database (Israel). Women aged 18-44 years old on July 1, 2013 with no record of pregnancy in the prior 6 months were followed through December 31, 2017 for first pregnancy occurrence. Pregnancy outcomes (live birth, spontaneous/therapeutic abortions, stillbirth, and uncertain outcomes) were captured. CMV test results were obtained to assess serostatus at the start of pregnancy (SoP) and primary CMV infection (CMVi) during pregnancy. Associations of demographic and reproductive factors with pCMVi were investigated (multivariable logistic regression). The study included 84 699 pregnant women (median age = 31 years; interquartile range = 28-35). Live birth, fetal loss, and uncertain pregnancy outcomes accounted for 76.8%, 18.2%, and 5.0%, respectively. The seroprevalence of CMV at the start of pregnancy in this cohort was 63.4% (95% confidence interval [CI]: 63.1-63.7). Among seronegative women with available test results (n = 10 657), CMVi incidence was 14.5 per 1000 (95% CI = 12.2-16.7). In multivariate logistic regression models adjusting for maternal age, CMVi was significantly associated with having one or more prior live births (odds ratio [OR]: 3.8 [95% CI: 2.6-5.4]) and having a child less than 6 years of age (OR: 4.3 [95%CI: 3.0-6.1]). One in three pregnant women in Israel is at risk for primary CMVi. This study demonstrates that real-world electronic healthcare data can be leveraged to support clinical management and development of interventions for congenital CMV by identifying women at high risk for CMVi during pregnancy.

De Garengeot’s hernia, the presence of an incarcerated vermiform appendix within a femoral hernia, is a rare general surgery emergency that predominantly affects elderly female patients. Due to its rarity, there is significant variation in surgical technique; however, most case reports favor an open approach. Here we present a case of a De Garengeot’s hernia with a unique hybrid open and laparoscopic repair, utilizing the hernia defect as a port site. We will also review the relevant literature.

Introduction Autonomy is of foremost concern in the current era of surgical residency, and it is especially important to trainees when considering their surgical education. Factors impacting trainee independence include the restriction of clinical work hours and the development of advanced minimally invasive techniques such as robotics, which requires separate technical education outside of conventional surgical education. Moreover, when residents are left to learn fundamental exposures via their clinical experience alone, they run the risk of not being exposed to some fundamental skills based on case volume and type. The Department of Surgery at Emory University developed a cadaver-based simulation curriculum to standardize exposure to fundamental operative skills and enhance proficiency outside the operating room, with the larger aim of improving resident autonomy. Methods Residents were assigned to small groups led by a chief resident with an even distribution of postgraduate year (PGY) levels. Each group participated in core surgical exposures and fundamental maneuvers on a cadaver over a 6-hour session. Residents were tested on skills according to their PGY level about 1 month after the course. Testing included recitation of the skill in an oral boards format, highlighting major steps, followed by performance of the skill. All steps were video-recorded with no resident identifiers. These were reviewed by 2 independent, blinded faculty examiners who assigned proficiency grades to each resident video. Results Three hundred and thirty-three individual procedure evaluations were done over the 5-year period. Senior residents (PGY3-5) had 86% pass rate while junior residents (PGY1-2) had 70% pass rate. Overall, 21% of residents failed to achieve competence in their assigned skills. Junior residents were less likely to achieve competence compared to senior residents. Faculty graders had improved congruence in grading as the course progressed through the 5 years. The most recent 2 years had >80% congruence in faculty grading compared to less than 50% congruence in the first 2 years. 81% of attendings agreed this course positively influenced the granting of autonomy in the operating room. Conclusions A cadaveric skills course focused on fundamental maneuvers with objective confirmation of achieving competency is a viable adjunct to clinical operative experience. Video-recorded evaluation, of these fundamental skills improved both resident and attending confidence in trainee operative skill.

One's personal physician, national and state or local public health officials, and the broader medical profession play important roles in encouraging vaccine uptake for COVID-19. However, the relationship between trust in these experts and vaccine hesitancy has been underexplored, particularly among racial/minority groups where historic medical mistrust may reduce uptake. Using an April 2021 online sample of US adults (n = 3041) that explored vaccine hesitancy, regression models estimate levels of trust in each of these types of experts and between trust in each of these experts and the odds of being COVID-19 vaccine takers vs refusers or hesitaters. Interaction terms assess how levels of trust in the medical profession by race/ethnicity are associated with vaccine hesitancy. Trust in each expert is positively associated with trust in other experts, except for trust in the medical profession. Only trust in one's own doctor was associated with trust in the medical profession, as measured by factor scores derived from a validated scale. Lower levels of trust in experts were significantly associated with being either a hesitater or a refuser compared to being a taker. Black respondents had higher odds of being either a hesitater or a refuser compared to white respondents but the interaction with trust was insignificant. For Hispanic respondents only, the odds of being a hesitater declined significantly when trust in the medical profession rose. Mistrust in the medical profession, one's doctor and national experts contributes to vaccine hesitancy. Mobilizing personal physicians to speak to their own patients may help.

Electroluminescence can be generated from a wide variety of emissive materials using a simple, generic device structure. In such a device, emissive materials are deposited by various means on a metal oxide semiconductor capacitor structure across which alternating current voltage is applied. However, these devices suffer from low external efficiencies and require the application of high voltages, thus hindering their practical usage and raising questions about the possible efficiencies that can be achieved using alternating current driving schemes in which injection of bipolar charges does not occur simultaneously. We show that appropriately chosen reactive electrical components can be leveraged to generate passive voltage gain across the device, allowing operation at input voltages below 1 V for devices across a range of gate oxide thicknesses. Furthermore, high power efficiencies are observed when using thermally activated delayed fluorescence emitters deposited by a single thermal evaporation step, suggesting that the efficiency of a light-emitting device with simplified structure can be high.

Advances in mobile app technologies offer opportunities for researchers to feasibly collect a large amount of patient data that were previously inaccessible through traditional clinical research methods. Collection of data via mobile devices allows for several advantages, such as the ability to continuously gather data outside of research facilities and produce a greater quantity of data, making these data much more valuable to researchers. Health services research is increasingly incorporating mobile health (mHealth), but collecting these data in current research institutions is not without its challenges. Our paper uses a specific example to depict specific challenges of mHealth research and provides recommendations for investigators looking to incorporate digital app technologies and patient-collected digital data into their studies. Our experience describes how clinical researchers should be prepared to work with variable software and mobile app development timelines; research institutions that are interested in participating in mHealth research need to invest in supporting information technology infrastructures in order to be a part of the growing field of mHealth and gain access to valuable patient-collected data.

UNSTRUCTURED Advances in mobile app technologies offer opportunities for researchers to feasibly collect a large amount of patient data that were previously inaccessible through traditional clinical research methods. Collection of data via mobile devices allows for several advantages, such as the ability to continuously gather data outside of research facilities and produce a greater quantity of data, making these data much more valuable to researchers. Health services research is increasingly incorporating mobile health (mHealth), but collecting these data in current research institutions is not without its challenges. Our paper uses a specific example to depict specific challenges of mHealth research and provides recommendations for investigators looking to incorporate digital app technologies and patient-collected digital data into their studies. Our experience describes how clinical researchers should be prepared to work with variable software and mobile app development timelines; research institutions that are interested in participating in mHealth research need to invest in supporting information technology infrastructures in order to be a part of the growing field of mHealth and gain access to valuable patient-collected data.

In the last decade, pharmaceutical manufacturing has been undergoing a modernization trend, promoted by the US Food and Drug Administration (FDA) with the Quality-by- Design (QbD) initiative. However, in most of the cases, the product quality is still controlled in open-loop, and pharmaceutical operation is carried out in the traditional batch mode, rather than continuously. In this work, we present a framework for closed- loop quality control of a novel continuous integrated filtration-drying unit. The unit addresses the current lack of technology for continuous drug substance isolation, which is the main bottleneck in end-to-end continuous pharmaceutical manufacturing. With the proposed closed-loop control framework, the product conformity is improved, showing how a Quality-by-Control (QbC) strategy can outperform earlier QbD approaches based on open-loop control.

Flowsheet design and optimization constitute one of the key challenges in the chemical engineering and process optimization communities. Software tools for digital design and flowsheet simulation are readily available for traditional chemical processing problems such as distillation and hydrocarbon processing, however tools for pharmaceutical manufacturing are much less widely developed. This paper introduces, PharmaPy, a Python-based modelling platform for pharmaceutical facility design and optimization. The versatility of the platform is demonstrated in simulating continuous, batch, and hybrid process flowsheets.

A commonly disputed medicolegal issue is the documentation of the location, degree, and anatomical source of an injured plaintiff’s ongoing pain, particularly when the painful region is in or near the spine, and when the symptoms have arisen as result of a relatively low speed traffic crash. The purpose of our paper is to provide health and legal practitioners with strategies to identify the source of cervical pain and to aid triers of fact (decision makers) in reaching better informed conclusions. We review the medical evidence for the applications and reliability of cervical medial branch nerve blocks as an indication of painful spinal facets. We also present legal precedents for the legal admissibility of the results of such diagnostic testing as evidence of chronic spine pain after a traffic crash. Part of the reason for the dispute is the subjective nature of pain, and the fact that medical documentation of pain complaints relies primarily on the history given by the patient. A condition that can be documented objectively is chronic cervical spine facet joint pain, as demonstrated by medial branch block (injection). The diagnostic accuracy of medial branch blocks has been extensively described in the scientific medical literature, and evidence of facet blocks to objectively document chronic post-traumatic neck pain has been accepted as scientifically reliable in courts and tribunals in the USA, Canada and the United Kingdom. We conclude that there is convincing scientific medical evidence that the results of cervical facet blocks provide reliable objective evidence of chronic post-traumatic spine pain, suitable for presentation to an adjudicative decision maker.

To describe current practices and safety concerns regarding cardiac emergency medications in cardiac anesthesia.An anonymous survey with multiple-choice questions.Online survey using Opinio platform.Cardiac anesthesiologists from United States and Canada.None.Response rate was 12% (n = 320), with 78% of respondents from the United States and 22% from Canada. The majority of the respondents were experienced (66%), academic (60%), and worked in large cardiac institutions (81%). Most cardiac emergency medications were prepared in the operating room (53.4%), followed by the pharmacy (34%) and industry (8.2%). American respondents had more medications prepared by a pharmacy (53%) versus Canadian (10%, p0.001). The majority (85%) considered expiration time of cardiac medications prepared in the operating room to be more than 12 hours. Familiarity with the American Society of Anesthesiologists guidelines on labeling was 58%, other medication safety guidelines 25%, and 34% were not familiar with any guidelines. The majority used color-coded labeling (95%), and a minority (11%) used bar-code systems. Most respondents (69%) agreed that lack of availability of preprepared medications could compromise patient safety. Having to prepare medications by themselves was a concern for respondents based on distractions (66%), lack of availability for emergencies (53%), labeling errors (41%), incorrect concentration (36%), sterility (33%), and stability (30%).This survey found that cardiac emergency medications commonly are prepared in the operating room. The authors identified gaps in familiarity with parenteral medications safety guidelines. Most safety concerns could be addressed with the application of current medication safety guidelines.

Early human allograft rejection can be initiated when circulating human host versus graft Ag-specific CD8 and CD4 effector memory T cells directly recognize MHC class I and II, respectively, expressed on the luminal surface by endothelium lining graft blood vessels. TCR engagement triggers both graft entry (TCR-driven transendothelial migration or TEM) and production of proinflammatory cytokines. Both TCR-driven TEM and cytokine expression are known to depend on T cell enzymes, myosin L chain kinase, and calcineurin, respectively, that are activated by cytoplasmic calcium and calmodulin, but whether the sources of calcium that control these enzymes are the same or different is unknown. Using superantigen or anti-CD3 Ab presented by cultured human dermal microvascular cells to freshly isolated peripheral blood human effector memory T cells under conditions of flow (models of alloantigen recognition in a vascularized graft), we tested the effects of pharmacological inhibitors of TCR-activated calcium signaling pathways on TCR-driven TEM and cytokine expression. We report that extracellular calcium entry via CRAC channels is the dominant contributor to cytokine expression, but paradoxically these same inhibitors potentiate TEM. Instead, calcium entry via TRPV1, L-Type Cav, and pannexin-1/P2X receptors appear to control TCR-driven TEM. These data reveal new therapeutic targets for immunosuppression.

Process design and optimization continue to provide computational challenges as the chemical engineering and process optimization communities seek to address more complex and larger scale applications. Software tools for digital design and flowsheet simulation are readily available for traditional chemical processing applications such as in commodity chemicals and hydrocarbon processing; however, tools for pharmaceutical manufacturing are much less well developed. This paper introduces, PharmaPy, a Python-based modelling platform for pharmaceutical manufacturing systems design and optimization. The versatility of the platform is demonstrated in simulation and optimization of both continuous and batch processes. The structure and features of a Python-based modeling platform, PharmaPy are presented. Illustrative examples are shown to highlight key features of the platform and framework.

The translocation of double-stranded DNA through a solid-state nanopore may either decrease or increase the ionic current depending on the ionic concentration of the surrounding solution. Below a certain crossover ionic concentration, the current change inverts from a current blockade to current enhancement. In this paper, we show that the crossover concentration for bundled DNA nanostructures composed of multiple connected DNA double-helices is lower than that of double-stranded DNA. Our measurements suggest that counterion mobility in the vicinity of DNA is reduced depending on the three-dimensional structure of the molecule. We further demonstrate that introducing neutral polymers such as polyethylene glycol into the measurement solution reduces electroosmotic outflow from the nanopore, allowing translocation of large DNA structures at low salt concentrations. Our experiments contribute to an improved understanding of ion transport in confined DNA environments, which is critical for the development of nanopore sensing techniques as well as synthetic membrane channels. Our salt-dependent measurements of model DNA nanostructures will guide the development of computational models of DNA translocation through nanopores.

Severely burned patients suffer from a hypermetabolic syndrome that can last for years after the injury has resolved. The underlying cause of these metabolic alterations most likely involves the persistent elevated catecholamine levels that follow the surge induced by thermal injury. At the cellular level, endoplasmic reticulum (ER) stress in metabolic tissues is a hallmark observed in patients following burn injury and is associated with several detrimental effects. Therefore, ER stress could be the underlying cellular mechanism of persistent hypermetabolism in burned patients. Here, we show that catecholamines induce ER stress and that adreno-receptor blockers reduce stress responses in the HepG2 hepatocyte cell line. Our results also indicate that norepinephrine (NE) significantly induces ER stress in HepG2 cells and 3T3L1 mouse adipocytes. Furthermore, we demonstrate that the alpha-1 blocker, prazosin, and beta blocker, propranolol, block ER stress induced by NE. We also show that the effects of catecholamines in inducing ER stress are cell type-specific, as NE treatment failed to evoke ER stress in human fibroblasts. Thus, these findings reveal the mechanisms used by catecholamines to alter metabolism and suggest inhibition of the receptors utilized by these agents should be further explored as a potential target for the treatment of ER stress-mediated disease.

We are currently investigating a non-invasive technique to determine collagen content and hydration in the skin by the optical methods of absorption, fluorescence and Raman spectroscopy for imaging. A major barrier to the effective use of skin therapies is the difficulty of quantifying existing collagen content and water content. Absorption of near infrared light by skin depends both on the concentration of collagen and the amount of water in the skin. In the near infrared (NIR window I) collagen and water have similar absorption profiles. However, because the infrared spectrum of collagen and water from 900 nm to 1700 nm (window II and III) are significantly different, it allows us to quantify collagen relative to water content. The ratio of the absorption of collagen normalized to water at 1700 nm and at 1950 nm (window III and window IV) is linear in collagen concentration. This can be used to discriminate between tissues by absorption imaging. We compare these results to Raman spectroscopy and native fluorescence. Our goal is to generate data that can be used for qualitative imaging allowing for improvement in assessing the effectiveness of skin-treatment therapies for the health care field to develop a device for home and medical office which can answer the age-old question: “Mirror, Mirror on the wall, where exactly should I apply skin therapeutics for maximum effectiveness and minimal side-effects?”

OBJECTIVE: The present study aims to investigate the alterations in monocytes (Mo) and dendritic cells (DCs) in septic burned patients with a special focus on C-C chemokine receptor type 2 (CCR2) expressions on classical Mo. BACKGROUND: The phenotypes of Mo and DCs, particularly CCR2 expression on Mo, are not fully explored in severely burned patients with sepsis. METHODS: The prospective cohort study was conducted at Ross Tilley Burn Centre and Sunnybrook Research Institute (Toronto, Canada). We enrolled 8 healthy patients and 89 burned patients with various burned sizes, of those burned patients, 12 suffered from profound sepsis. Blood was collected upon admission to the hospital and throughout their course in hospital. The expression of human leukocyte antigen-DR was determined on all DCs and Mo, along with CCR2 on CD14(++)/CD16(−) Mo. RESULTS: We found a profound decrease in human leukocyte antigen-DR on Mo and DCs in burned patients with sepsis compared with healthy controls and nonseptic burned patients. In addition, septic burned patients presented an increased CCR2 expression on classical Mo (CD14(++)/CD16(−)), which was paralleled by greater chemokine (C-C motif) ligand 2 concentrations in the plasma when compared with controls and nonseptic burned patients. Furthermore, burned patients with sepsis had a more profound expansion of CD14(++)/CD16(+) Mo when compared with nonseptic burned patients. CONCLUSION: Our results demonstrate that burned patients with sepsis have a significant increased impairment of monocytes and dendritic cells than burned patients without sepsis. With CCR2 level on Mo before sepsis onset being higher than postsepsis, CCR2 expression could be a new predictor of sepsis onset in severe burn injury.

The use of an alternating current (AC) voltage is a simple, versatile method of producing electroluminescence from generic emissive materials without the need for contact engineering. Recently, it was shown that AC-driven, capacitive electroluminescent devices with carbon nanotube network contacts can be used to generate and study electroluminescence from a variety of molecular materials emitting in the infrared-to-ultraviolet range. Here, performance trade-offs in these devices are studied through comprehensive device simulations and illustrative experiments, enhancing understanding of the mechanism and capability of electroluminescent devices based on alternating as opposed to direct current (DC) schemes. AC-driven electroluminescent devices can overcome several limitations of conventional DC-driven electroluminescent devices, including the requirement for proper alignment of material energy levels and the need to process emitting materials into uniform thin films. By simultaneously optimizing device geometry, driving parameters, and material characteristics, the performance of these devices can be tuned. Importantly, the turn-on voltage of AC-driven electroluminescent devices approaches the bandgap of the emitting material as the gate oxide thickness is scaled, and internally efficient electroluminescence can be achieved using low-mobility single-layer emitter films with varying thicknesses and energy barrier heights relative to the contact.