Sex-based Differences in the Lung Immune Microenvironment Are Associated with an Increased Risk of Lung Cancer in Women.

OBJECTIVE: Lung cancer remains a major cause of mortality worldwide, necessitating further understanding of carcinogenesis and its driving factors, including those impacted by sex-dependent variables. We hypothesized that sex-specific lung immune composition may contribute to a greater risk of lung cancer in females. METHODS: Data from 1056 lung cancer screenings were examined for an association between sex and lung cancer risk using time-to-event analyses. Immune profiling by flow cytometry was performed on male and female lungs of three independent mouse models: non-tumor bearing, K-ras mutated, and urethane-exposed carcinogenic. A comparable analysis was performed on human bronchoalveolar lavage samples (n = 81) from lung cancer patients. RESULTS: Of the high-risk screening cohort examined, 60 patients (5.7%) developed lung cancer during median follow-up of 43.4 months. Multivariable stepwise modeling retained female sex (hazard ratio 1.56, P < 0.01) and age (P < 0.01) as prognostic indicators for lung cancer development. Female lung immune profiles in patients included T cell phenotypes consistent with exhaustion (e.g., higher proportions of PD-1+ Ki67-; P = 0.02), an expanded pool of regulatory T cells (P = 0.03), reduced effector T cell frequencies (P = 0.008), and enhancements in suppressive myeloid populations (P = 0.02) versus males, and this is recapitulated in mouse studies. CONCLUSIONS: Female smokers display higher risk for lung cancer. In murine models and humans, female sex is associated with robust immunosuppression within the lung. Further examination of this link will be important in developing immune-based approaches to lung cancer interception and their optimal application across the sexes.

Empowering and Educating the Next Generation of Pharmacists through Children's Books: A Quality Assurance Initiative.

OBJECTIVE: The objective of this quality assurance initiative was to internally measure children's perceptions of the book, "All Aboard the Rx-Express!" and knowledge gained from its content. METHODS: This pharmacy-focused children's book was read to elementary-age youth at a rural, Pennsylvania elementary school in the Spring of 2022. A brief, optional, anonymous pre-post survey was administered to the youth before and after the reading to measure the book's impact on third through fifth graders' perceptions and knowledge of the pharmacy profession. Descriptive statistics, chi squared analysis, independent samples t-tests, and one sample proportions tests were used to analyze survey responses. RESULTS: One hundred ninety-one students participated in the pre-survey to assess baseline knowledge about the pharmacy profession before the book was read. One hundred eighty-five students answered the post-survey. Pre-post respondent demographics were collected in aggregate and were not significantly different between the pre- and post-cohorts. Survey results demonstrated an increase in all questions that asked about students' perceptions of pharmacists and the profession, and students reported favorable perceptions of the book itself. CONCLUSION: Early interventions such as this can increase elementary-age youth's perceptions and knowledge of the roles of pharmacists. Future work in early intervention will be needed to increase interest in the profession and admissions to pharmacy schools.

Harnessing the potential of monocytes/macrophages to regenerate tissue-engineered vascular grafts.

Cell-free tissue-engineered vascular grafts provide a promising alternative to treat cardiovascular disease, but timely endothelialization is essential for ensuring patency and proper functioning post-implantation. Recent studies from our lab showed that blood cells like monocytes (MCs) and macrophages (Mϕ) may contribute directly to cellularization and regeneration of bioengineered arteries in small and large animal models. While MCs and Mϕ are leucocytes that are part of the innate immune response, they share common developmental origins with endothelial cells (ECs) and are known to play crucial roles during vessel formation (angiogenesis) and vessel repair after inflammation/injury. They are highly plastic cells that polarize into pro-inflammatory and anti-inflammatory phenotypes upon exposure to cytokines and differentiate into other cell types, including EC-like cells, in the presence of appropriate chemical and mechanical stimuli. This review focuses on the developmental origins of MCs and ECs; the role of MCs and Mϕ in vessel repair/regeneration during inflammation/injury; and the role of chemical signalling and mechanical forces in Mϕ inflammation that mediates vascular graft regeneration. We postulate that comprehensive understanding of these mechanisms will better inform the development of strategies to coax MCs/Mϕ into endothelializing the lumen and regenerate the smooth muscle layers of cell-free bioengineered arteries and veins that are designed to treat cardiovascular diseases and perhaps the native vasculature as well.

"There isn't anybody else like me around here": the insider-outsider status of LGBT residents in housing with care schemes for older people.

The intersections between aging, social minority status and housing needs in later life is a neglected area of sociological exploration, even more so for older people who identify as lesbian, gay, bisexual and trans (LGBT). Recent sociological findings indicate that older LGBT people in housing schemes stress the importance of bonding social capital and look to other people in their social networks who reflect their identities and experiences as sources of support. In this paper, we examine the insider-outsider status occupied by older LGBT residents living in housing schemes that provide some form of care and support, for example extra care and independent living schemes. We present qualitative findings generated from a mixed-methods study of social inclusion practices in housing with care in England and Wales (UK) (2019-22). In this study 15 LGBT residents participated in semi-structured interviews (55-79 years of age) across a total of 31 interviews. Through a queer gerontological lens we examine how older LGBT people are socially situated within mainstream housing schemes in which they experience partial visibility while also encountering exclusionary pressures that locate them as "the other." This insider-outsider status undermines the premise of housing with care schemes to provide safe, secure spaces to grow old. We discuss three core themes: (1) how LGBT residents navigate their outsider status in scheme life and how the intersection of disability and minority status amplifies this social location; (2) the exclusionary practices exercised by other residents that reinforce boundaries of sexual and gender normalcy; and, (3) the heightened importance of maintaining external social connections among LGBT residents. We conclude by introducing an alternative notion of marginal aging and expanding on the implications for housing providers, reflecting on their responsibilities for promoting and maintaining queer-friendly environments.

The impact of COVID-19 lockdown measures on older residents' social connections and everyday wellbeing within housing schemes that provide care and support in England and Wales.

The COVID-19 pandemic and the lockdown measures imposed as a result affected the lives of people in all parts of society across the world. In 2020, during the first UK national lockdown, older adults (aged 70 years and over) were told to 'shield' within their homes, as they were regarded as being at higher risk of serious COVID-19 infection compared to other age groups. This paper explores older adults' experiences of COVID-19 lockdown measures whilst living in housing with care schemes for older people. The purpose is to examine the impact of the lockdown measures on scheme life including social connections amongst residents and their general everyday wellbeing during this time. We present qualitative findings based on interviews with 72 residents who took part in longitudinal and cross-sectional interviews across 26 housing with care schemes. Data were analysed using a thematic framework approach to examine specifically their experiences of living in housing with care schemes during the 2020 UK lockdown. The paper highlights that COVID-19 restrictions had a detrimental impact on the social connections and interactions of older residents living in housing with care schemes, as well as on their feelings of autonomy and independence. Despite this, residents adapted and coped with self-isolation restrictions and sought out positive ways to maintain social contact with others inside and outside to the scheme. We further highlight the tensions that providers of housing for older adults faced in promoting residents' autonomy and connectedness whilst also trying to provide a safe living environment and protect residents from risk of COVID-19 infection. Our findings apply not only to a pandemic situation but to the broader understanding of how housing with care for older adults must navigate between autonomy and support.

Immunoprofiling bronchoalveolar lavage cells reveals multifaceted smoking-associated immune dysfunction.

Background: Bronchoalveolar lavage (BAL) is an underutilised tool in the search for pulmonary disease biomarkers. While leukocytes with effector and suppressor function play important roles in airway immunity and tumours, it remains unclear if frequencies and phenotypes of BAL leukocytes can be useful parameters in lung cancer studies and clinical trials. We therefore explored the utility of BAL leukocytes as a source of biomarkers interrogating the impact of smoking, a major lung cancer risk determinant, on pulmonary immunity. Methods: In this "test case" observational study, BAL samples from 119 donors undergoing lung cancer screening and biopsy procedures were evaluated by conventional and spectral flow cytometry to exemplify the comprehensive immune analyses possible with this biospecimen. Proportions of major leukocyte populations and phenotypic markers levels were found. Multivariate linear rank sum analysis considering age, sex, cancer diagnosis and smoking status was performed. Results: Significantly increased frequencies of myeloid-derived suppressor cells and PD-L1-expressing macrophages were found in current and former smokers compared to never-smokers. While cytotoxic CD8 T-cells and conventional CD4 helper T-cell frequencies were significantly reduced in current and former smokers, expression of immune checkpoints PD-1 and LAG-3 as well as Tregs proportions were increased. Lastly, the cellularity, viability and stability of several immune readouts under cryostorage suggested BAL samples are useful for correlative end-points in clinical trials. Conclusions: Smoking is associated with heightened markers of immune dysfunction, readily assayable in BAL, that may reflect a permissive environment for cancer development and progression in the airway.

The Impact of Living in Housing With Care and Support on Loneliness and Social Isolation: Findings From a Resident-Based Survey.

Background and Objectives: Housing with care is often lauded as a way to combat loneliness and social isolation in later life. This study examined whether housing with care created better outcomes for residents in terms of loneliness and social isolation than they might expect if they were living in the community. Research Design and Methods: A survey was distributed to residents of housing with care as part of the Diversity in Care Environments project. It was designed to enable comparison with the English Longitudinal Study of Ageing. Propensity score matching was applied to identify the effect of housing with care residence on loneliness and social isolation. Results: People living in housing with care had lower levels of loneliness than would be expected if they lived in the general community, with an average treatment effect on the treated (ATT) of -0.407 (95% CI = -0.601, -0.214). In contrast, social isolation was found to be slightly higher for residents than would be expected if they were in the community (ATT = 0.134 [95% CI = 0.022, 0.247]). Higher social isolation appears driven by less frequent contact with friends and reduced organizational membership rather than any difference in contact with family and children. Discussion and Implications: Our research has shown a positive impact on subjective social experiences from housing with care residence, despite a slight increase in objective social isolation. The findings underscore the importance of looking at loneliness and social isolation as distinct concepts as well as the effectiveness of housing with care at improving later-life outcomes.

Project-based learning through sensor characterization in a musical acoustics course.

Project-based learning engages students in practical activities related to course content and has been demonstrated to improve academic performance. Due to its reported benefits, this form of active learning was incorporated with an ongoing research project into an introductory, graduate-level Musical Acoustics course at the Peabody Institute of The Johns Hopkins University. Students applied concepts from the course to characterize a contact sensor with a polymer diaphragm for musical instrument recording. Assignments throughout the semester introduced students to completing a literature review, planning an experiment, collecting and analyzing data, and presenting results. While students were given broad goals to understand the performance of the contact sensor compared to traditional microphones, they were allowed independence in determining the specific methods used. The efficacy of the course framework and research project was assessed with student feedback provided through open-ended prompts and Likert-type survey questions. Overall, the students responded positively to the project-based learning and demonstrated mastery of the course learning objectives. The work provides a possible framework for instructors considering using project-based learning through research in their own course designs.

Altered acetyl-CoA metabolism presents a new potential immunotherapy target in the obese lung microenvironment.

Contrary to the "obesity paradox," which arises from retrospective studies relying on body mass index to define obesity, epidemiologic evidence suggests central or visceral obesity is associated with a higher risk for the development of lung cancer. About 60% of individuals at high risk for developing lung cancer or those already with early-stage disease are either overweight or obese. Findings from resected patient tumors and mouse lung tumor models show obesity dampens immune activity in the tumor microenvironment (TME) encouraging disease progression. In line with this, we have observed a marked, obesity-specific enhancement in the presence and phenotype of immunosuppressive regulatory T (Treg) cells in murine tumors as well as the airways of both humans and mice. Leveraging direct metabolomic measurements and robust inferred analyses from RNA-sequencing data, we here demonstrate for the first time that visceral adiposity alters the lung microenvironment via dysregulated acetyl-CoA metabolism in a direction that facilitates immune suppression and lung carcinogenesis.

Monocyte Recruitment for Vascular Tissue Regeneration.

A strategy to recruit monocytes (MCs) from blood to regenerate vascular tissue from unseeded (cell-free) tissue engineered vascular grafts is presented. When immobilized on the surface of vascular grafts, the fusion protein, H2R5 can capture blood-derived MC under static or flow conditions in a shear stress dependent manner. The bound MC turns into macrophages (Mϕ) expressing both M1 and M2 phenotype specific genes. When H2R5 functionalized acellular-tissue engineered vessels (A-TEVs) are implanted into the mouse aorta, they remain patent and form a continuous endothelium expressing both endothelial cell (EC) and MC specific proteins. Underneath the EC layer, multiple cells layers are formed coexpressing both smooth muscle cell (SMC) and MC specific markers. Lineage tracing analysis using a novel CX3CR1-confetti mouse model demonstrates that fluorescently labeled MC populates the graft lumen by two and four weeks postimplantation, providing direct evidence in support of MC/Mϕ recruitment to the graft lumen. Given their abundance in the blood, circulating MCs may be a great source of cells that contribute directly to the endothelialization and vascular wall formation of acellular vascular grafts under the right chemical and biomechanical cues.

Generating Monocyte-Derived Endothelial-like Cells for Vascular Regeneration.

A major limitation in engineering vascular grafts is the lack of proper endothelium to prevent thrombosis and subsequent graft failure. Obtaining endothelial cells from patients' vasculature is intrusive and requires extensive culture time. Here we present an alternative strategy wherein abundant and easily accessible monocytes from peripheral blood are cultured and differentiated towards an endothelial-like state capable of preventing thrombosis through production of nitric oxide and formation of endothelial adherens junctions. Considering the plethora of monocytes present within peripheral blood, this method provides a robust alternative to generating endothelial cells required for vascular graft production.

Aging augments obesity-induced thymic involution and peripheral T cell exhaustion altering the "obesity paradox".

Introduction: The incidence of obesity, a condition characterized by systemic chronic inflammation, has reached pandemic proportions and is a poor prognostic factor in many pathologic states. However, its role on immune parameters has been diverse and at times contradictory. We have previously demonstrated that obesity can result in what has been called the "obesity paradox" which results in increased T cell exhaustion, but also greater efficacy of immune checkpoint blockade in cancer treatment. Methods: The role of obesity, particularly in the context of aging, has not been robustly explored using preclinical models. We therefore evaluated how age impacts the immune environment on T cell development and function using diet-induced obese (DIO) mice. Results: We observed that DIO mice initially displayed greater thymopoiesis but then developed greater thymic involution over time compared to their lean counterparts. Both aging and obesity resulted in increased T cell memory conversion combined with increased expression of T cell exhaustion markers and Treg expansion. This increased T cell immunosuppression with age then resulted in a loss of anti-tumor efficacy by immune checkpoint inhibitors (ICIs) in older DIO mice compared to the younger DIO counterparts. Discussion: These results suggest that both aging and obesity contribute to T cell dysfunction resulting in increased thymic involution. This combined with increased T cell exhaustion and immunosuppressive parameters affects immunotherapy efficacy reducing the advantage of obesity in cancer immunotherapy responses.

Visceral Obesity Promotes Lung Cancer Progression-Toward Resolution of the Obesity Paradox in Lung Cancer.

INTRODUCTION: Although obesity is associated with adverse cancer outcomes in general, most retrospective clinical studies suggest a beneficial effect of obesity in NSCLC. METHODS: Hypothesizing that this "obesity paradox" arises partly from the limitations of using body mass index (BMI) to measure obesity, we quantified adiposity using preoperative computed tomography images. This allowed the specific determination of central obesity as abdominal visceral fat area normalized to total fat area (visceral fat index [VFI]). In addition, owing to the previously reported salutary effect of metformin on high-BMI patients with lung cancer, metformin users were excluded. We then explored associations between visceral obesity and outcomes after surgical resection of stage I and II NSCLC. We also explored potential immunologic underpinnings of such association using complimentary analyses of tumor gene expression data from NSCLC tumors and the tumor transcriptome and immune microenvironment in an immunocompetent model of lung cancer with diet-induced obesity. RESULTS: We found that in 513 patients with stage I and II NSCLC undergoing lobectomy, a high VFI is associated with decreased recurrence-free and overall survival. VFI was also inversely related to an inflammatory transcriptomic signature in NSCLC tumors, consistent with observations made in immunocompetent murine models wherein diet-induced obesity promoted cancer progression while exacerbating elements of immune suppression in the tumor niche. CONCLUSIONS: In all, this study uses multiple lines of evidence to reveal the adverse effects of visceral obesity in patients with NSCLC, which align with those found in animal models. Thus, the obesity paradox may, at least in part, be secondary to the use of BMI as a measure of obesity and the confounding effects of metformin use.

MCCS: a novel recognition pattern-based method for fast track discovery of anti-SARS-CoV-2 drugs.

Given the scale and rapid spread of the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, or 2019-nCoV), there is an urgent need to identify therapeutics that are effective against COVID-19 before vaccines are available. Since the current rate of SARS-CoV-2 knowledge acquisition via traditional research methods is not sufficient to match the rapid spread of the virus, novel strategies of drug discovery for SARS-CoV-2 infection are required. Structure-based virtual screening for example relies primarily on docking scores and does not take the importance of key residues into consideration, which may lead to a significantly higher incidence rate of false-positive results. Our novel in silico approach, which overcomes these limitations, can be utilized to quickly evaluate FDA-approved drugs for repurposing and combination, as well as designing new chemical agents with therapeutic potential for COVID-19. As a result, anti-HIV or antiviral drugs (lopinavir, tenofovir disoproxil, fosamprenavir and ganciclovir), antiflu drugs (peramivir and zanamivir) and an anti-HCV drug (sofosbuvir) are predicted to bind to 3CLPro in SARS-CoV-2 with therapeutic potential for COVID-19 infection by our new protocol. In addition, we also propose three antidiabetic drugs (acarbose, glyburide and tolazamide) for the potential treatment of COVID-19. Finally, we apply our new virus chemogenomics knowledgebase platform with the integrated machine-learning computing algorithms to identify the potential drug combinations (e.g. remdesivir+chloroquine), which are congruent with ongoing clinical trials. In addition, another 10 compounds from CAS COVID-19 antiviral candidate compounds dataset are also suggested by Molecular Complex Characterizing System with potential treatment for COVID-19. Our work provides a novel strategy for the repurposing and combinations of drugs in the market and for prediction of chemical candidates with anti-COVID-19 potential.

Assessment of Physician Sleep and Wellness, Burnout, and Clinically Significant Medical Errors.

Importance: Sleep-related impairment in physicians is an occupational hazard associated with long and sometimes unpredictable work hours and may contribute to burnout and self-reported clinically significant medical error. Objective: To assess the associations between sleep-related impairment and occupational wellness indicators in physicians practicing at academic-affiliated medical centers and the association of sleep-related impairment with self-reported clinically significant medical errors, before and after adjusting for burnout. Design, Setting, and Participants: This cross-sectional study used physician wellness survey data collected from 11 academic-affiliated medical centers between November 2016 and October 2018. Analysis was completed in January 2020. A total of 19 384 attending physicians and 7257 house staff physicians at participating institutions were invited to complete a wellness survey. The sample of responders was used for this study. Exposures: Sleep-related impairment. Main Outcomes and Measures: Association between sleep-related impairment and occupational wellness indicators (ie, work exhaustion, interpersonal disengagement, overall burnout, and professional fulfillment) was hypothesized before data collection. Assessment of the associations of sleep-related impairment and burnout with self-reported clinically significant medical errors (ie, error within the last year resulting in patient harm) was planned after data collection. Results: Of all physicians invited to participate in the survey, 7700 of 19 384 attending physicians (40%) and 3695 of 7257 house staff physicians (51%) completed sleep-related impairment items, including 5279 women (46%), 5187 men (46%), and 929 (8%) who self-identified as other gender or elected not to answer. Because of institutional variation in survey domain inclusion, self-reported medical error responses from 7538 physicians were available for analyses. Spearman correlations of sleep-related impairment with interpersonal disengagement (r = 0.51; P < .001), work exhaustion (r = 0.58; P < .001), and overall burnout (r = 0.59; P < .001) were large. Sleep-related impairment correlation with professional fulfillment (r = -0.40; P < .001) was moderate. In a multivariate model adjusted for gender, training status, medical specialty, and burnout level, compared with low sleep-related impairment levels, moderate, high, and very high levels were associated with increased odds of self-reported clinically significant medical error, by 53% (odds ratio, 1.53; 95% CI, 1.12-2.09), 96% (odds ratio, 1.96; 95% CI, 1.46-2.63), and 97% (odds ratio, 1.97; 95% CI, 1.45-2.69), respectively. Conclusions and Relevance: In this study, sleep-related impairment was associated with increased burnout, decreased professional fulfillment, and increased self-reported clinically significant medical error. Interventions to mitigate sleep-related impairment in physicians are warranted.

Endothelialization of arterial vascular grafts by circulating monocytes.

Recently our group demonstrated that acellular tissue engineered vessels (A-TEVs) comprised of small intestinal submucosa (SIS) immobilized with heparin and vascular endothelial growth factor (VEGF) could be implanted into the arterial system of a pre-clinical ovine animal model, where they endothelialized within one month and remained patent. Here we report that immobilized VEGF captures blood circulating monocytes (MC) with high specificity under a range of shear stresses. Adherent MC differentiate into a mixed endothelial (EC) and macrophage (Mφ) phenotype and further develop into mature EC that align in the direction of flow and produce nitric oxide under high shear stress. In-vivo, newly recruited cells on the vascular lumen express MC markers and at later times they co-express MC and EC-specific proteins and maintain graft patency. This novel finding indicates that the highly prevalent circulating MC contribute directly to the endothelialization of acellular vascular grafts under the right chemical and biomechanical cues.

Cell-free vascular grafts that grow with the host.

Cell-free small diameter vascular grafts, based on small intestinal submucosa (SIS) functionalized with heparin and vascular endothelial growth factor (VEGF) manufactured and implanted successfully into the arterial system of neonatal lambs, where they remained patent and grew in size with the host to a similar extent and with similar rate as native arteries. Acellular tissue engineered vessels (A-TEV) integrated seamlessly into the native vasculature and developed confluent, functional endothelium that afforded patency. The medial layer was infiltrated by smooth muscle cells, showed no signs of calcification and developed contractile function. The vascular wall underwent remarkable extracellular matrix remodeling exhibiting elastin fibers and even inner elastic lamina within six months. Taken together, our results suggest that VEGF-based A-TEVs may be suitable for treatment of congenital heart disorders to alleviate the need for repeated surgeries, which are currently standard practice.

Can extra care housing support the changing needs of older people living with dementia?

With over two-thirds of people with dementia living in the community and one-third of those living alone, it is important to consider the future housing needs of this population, particularly as symptoms of cognitive impairment increase. Policy in England has focused on enabling people living with dementia to remain in their own homes for as long as possible, often with the support of a family carer. However, many people struggle to maintain an acceptable quality of life in their own homes as their dementia advances, often due to the design limitations of mainstream housing and the challenge of finding specialist domiciliary care that is affordable and of sufficient quality. Extra care housing offers a model that aims to support older people living in their own apartments, whilst also offering specialist person-centred care as and when it is needed. This paper reports on a longitudinal project that explored how extra care housing can respond to the changing social care needs of residents, including those living with dementia. Participants included residents and staff from four extra care housing schemes, one of which was a specialist dementia scheme, in two regions of England. Interviews were carried with 51 residents across 4 rounds at 5 month intervals between October 2015 and June 2017. Interviews were also carried out with 7 managers, 20 care staff and 2 local authority commissioners of housing for older people. Key factors included person-centred care and support, flexible commissioning and staffing, appropriate design of the environment and suitable location of the scheme within the wider community. The challenge of delivering services that addresses these issues during a period of reduced public spending is acknowledged. Further research is suggested to compare different approaches to supporting people with dementia, including integrated and separated accommodation, and different stages of dementia.

'You have got to stick to your times': Care workers and managers' experiences of working in extra care housing.

Extra care housing (ECH) has been lauded as an innovative model of housing with care for older people that promotes and supports independent living. The study used a qualitative design to explore how care is delivered in four extra care settings in England over 20 months during 2016-2017. This paper reports findings from semi-structured interviews with 20 care workers and seven managers. The article argues that, despite being heralded as a new model, care workers in ECH face similar organisational pressures as those working in more conventional settings and, in turn, the care which they are able to provide to residents mimics traditional forms of care.