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Abstract Background Healthcare fragmentation and lack of care coordination are longstanding problems in cancer care. This study’s goal was to provide in-depth understanding of how the organization and fragmentation of healthcare impacts the experiences of patients with advanced cancer and their families, especially near the end-of-life. Methods This mixed-methods quality improvement study took place at a large multi-specialty healthcare organization in Northern California. Electronic health record data was used to identify patients with advanced cancer and their characteristics. Data were collected 10/2019-05/2022 through periodic patient surveys and in-depth interviews with sampled family members, including open-ended questions about overall healthcare experiences. Data were analyzed using inductive thematic analysis. Results Overall, 281/482 (58.3%) patients with advanced cancer completed surveys. Surveyed patients’ mean age was 68 (SD: 12.8) years, 53% were male, 73% White, 14.2% Asian, 1.4% Black, 3.9% Other; 8.9% Hispanic, and 19.2% were deceased within 12 months. Twenty-four family members completed in-depth interviews: 17/24 (70.8%) were spouses, 62.5% were female and 50% were interviewed after the patient’s death. Respondents were generally positive about health care team interactions, but consistently brought up the negative impacts of the organization of healthcare, “It is not the fault of the health care team - it is the way the system works.” Three major challenges were identified. (1) Systemic healthcare care fragmentation, including difficulties navigating care across providers and institutions, “It seems like everything is like an isolated incident… there’s no overall, big picture viewpoint.” (2) Administrative burdens, “In the end I gave up [scheduling care] because I was tired of calling.” (3) Financial burdens, “This oncologist wanted to put him on a drug…but it was $4000 a month.” Respondents described these challenges leading to worse quality of care, health, and quality of life, and loss of trust in the national healthcare system. Conclusions These findings illustrate how care fragmentation and administrative and financial burdens lead to worse quality care and distrust of healthcare. Better coordination of patient-centered care, and a fundamental restructuring of a highly fragmented national healthcare system are required to meet the needs of patients with complex conditions like advanced cancer and their families.

Abstract Single-cell multi-omics data reveal complex cellular states, providing significant insights into cellular dynamics and disease. Yet, integration of multi-omics data presents challenges. Some modalities have not reached the robustness or clarity of established transcriptomics. Coupled with data scarcity for less established modalities and integration intricacies, these challenges limit our ability to maximize single-cell omics benefits. We introduce scCross, a tool leveraging variational autoencoders, generative adversarial networks, and the mutual nearest neighbors (MNN) technique for modality alignment. By enabling single-cell cross-modal data generation, multi-omics data simulation, and in silico cellular perturbations, scCross enhances the utility of single-cell multi-omics studies.

Background E-cigarette use is now prevalent among adolescents and young adults, raising concerns over potential adverse long-term health effects. Although it is hypothesised that e-cigarettes promote inflammation, studies have yielded conflicting evidence. Our previous work showed that JUUL, a popular e-cigarette brand, elicited minimal lung inflammation but induced significant molecular changes in adult C57BL/6 mice.Methods Now, we have profiled immunological and proteomic changes in the lungs of adolescent male and female BALB/c and C57BL/6 mice exposed to a flavoured JUUL aerosol containing 18 mg/mL of nicotine for 14 consecutive days. We evaluated changes in the immune composition by flow cytometry, gene expression levels by reverse transcription-quantitative PCR and assessed the proteomic profile of the lungs and bronchoalveolar lavage (BAL) by tandem mass tag-labelled mass spectroscopy.Results While there were few significant changes in the immune composition of the lungs, proteomic analysis revealed that JUUL exposure caused significant sex-dependent and strain-dependent differences in lung and BAL proteins that are implicated in metabolic pathways, including those related to lipids and atherosclerosis, as well as pathways related to immune function and response to xenobiotics. Notably, these changes were more pronounced in male mice.Conclusions These findings raise the possibility that vaping dysregulates numerous biological responses in lungs that may affect disease risk, disproportionally impacting males and raising significant concerns for the future health of male youth who currently vape.

Abstract Background The tumour microenvironment (TME) consists of tumour-supportive immune cells, endothelial cells, and fibroblasts. PhenoCycler, a high-plex single cell spatial biology imaging platform, is used to characterize the complexity of the TME. Researchers worldwide harvest and bank tissues from mouse models which are employed to model a plethora of human disease. With the explosion of interest in spatial biology, these panoplies of archival tissues provide a valuable resource to answer new questions. Here, we describe our protocols for developing tunable PhenoCycler multiplexed imaging panels and describe our open-source data analysis pipeline. Using these protocols, we used PhenoCycler to spatially resolve the TME of 8 routinely employed pre-clinical models of lymphoma, breast cancer, and melanoma preserved as FFPE. Results Our data reveal distinct TMEs in the different cancer models that were imaged and show that cell-cell contacts differ depending on the tumour type examined. For instance, we found that the immune infiltration in a murine model of melanoma is altered in cellular organization in melanomas that become resistant to αPD-1 therapy, with depletions in a number of cell-cell interactions. Conclusions This work presents a valuable resource study seamlessly adaptable to any field of research involving murine models. The methodology described allows researchers to address newly formed hypotheses using archival materials, bypassing the new to perform new mouse studies.

Objectives The objective of this study is to evaluate whether anti-neutrophil cytoplasmic antibody (ANCA) seropositivity and antigen specificity at diagnosis have predictive utility in paediatric-onset small vessel vasculitis.Methods Children and adolescents with small vessel vasculitis (n=406) stratified according to the absence (n=41) or presence of ANCA for myeloperoxidase (MPO) (n=129) and proteinase-3 (PR3) (n=236) were compared for overall and kidney-specific disease activity at diagnosis and outcomes between 1 and 2 years using retrospective clinical data from the ARChiVe/Paediatric Vasculitis Initiative registry to fit generalised linear models.Results Overall disease activity at diagnosis was higher in PR3-ANCA and MPO-ANCA-seropositive individuals compared with ANCA-negative vasculitis. By 1 year, there were no significant differences, based on ANCA positivity or specificity, in the likelihood of achieving inactive disease (~68%), experiencing improvement (≥87%) or acquiring damage (~58%). Similarly, and in contrast to adult-onset ANCA-associated vasculitis, there were no significant differences in the likelihood of having a relapse (~11%) between 1 and 2 years after diagnosis. Relative to PR3-ANCA, MPO-ANCA seropositivity was associated with a higher likelihood of kidney involvement (OR 2.4, 95% CI 1.3 to 4.7, p=0.008) and severe kidney dysfunction (Kidney Disease Improving Global Outcomes (KDIGO) stages 4–5; OR 6.04, 95% CI 2.77 to 13.57, p

Abstract Antigen-naive IgM-producing B cells are atheroprotective, whereas mature B cells producing class-switched antibodies promote atherosclerosis. Activation-induced cytidine deaminase (AID), which mediates class switch recombination (CSR), would thus be expected to foster atherosclerosis. Yet, AID also plays a major role in the establishment of B cell tolerance. We sought to define whether AID affects atherosclerotic plaque formation. We generated Ldlr -/- chimeras transplanted with bone marrow from Aicda -/- or wild-type (WT) mice, fed a HFD for 14 weeks. Decreased B cell maturation in Ldlr -/- Aicda -/- mice was demonstrated by 50% reduction in splenic and aortic BAFFR expression, a key signaling component of B2 cell maturation. This was associated with increased plasma IgM in Ldlr –/- Aicda -/- compared with Ldlr -/- WT animals. Importantly, Ldlr -/- Aicda -/- mice had reduced atherosclerotic lesion area (0.20 ± 0.03mm2) compared with Ldlr -/- WT (0.30 ± 0.04mm2, P

Introduction: Evidence suggests that e-cigarette use (vaping) increases cardiovascular disease risk, but decades are needed before people who vape would develop pathology. Thus, murine models of atherosclerosis can be utilized as tools to understand disease susceptibility, risk and pathogenesis. Moreover, there is a poor understanding of how risk factors for atherosclerosis (i.e., hyperlipidemia, high-fat diet) intersect with vaping to promote disease risk. Herein, we evaluated whether there was early evidence of atherosclerosis in an inducible hyperlipidemic mouse exposed to aerosol from commercial pod-style devices and e-liquid.Methods: Mice were injected with adeno-associated virus containing the human protein convertase subtilisin/kexin type 9 (PCSK9) variant to promote hyperlipidemia. These mice were fed a high-fat diet and exposed to room air or aerosol derived from JUUL pods containing polyethylene glycol/vegetable glycerin (PG/VG) or 5% nicotine with mango flavoring for 4 weeks; this timepoint was utilized to assess markers of atherosclerosis that may occur prior to the development of atherosclerotic plaques.Results: These data show that various parameters including weight, circulating lipoprotein/glucose levels, and splenic immune cells were significantly affected by exposure to PG/VG and/or nicotine-containing aerosols.Discussion: Not only can this mouse model be utilized for chronic vaping studies to assess the vascular pathology but these data support that vaping is not risk-free and may increase CVD outcomes later in life.

The transition to a decarbonized economy will drive dramatically higher demand for energy storage, along with technological diversification. To avoid mistakes of the past, the supply chain implications and environmental and social justice (ESJ) impacts of new battery technologies should be considered early during technological development. We propose herein a systematic framework for analyzing these impacts for new stationary battery technologies and illustrate the framework with a case study. The goal is to promote future development of technologies with secure supply chains and favorable ESJ profiles to avoid expensive corrective actions after substantial resources have been invested. This framework should be a useful tool for public and private researchers and sponsors who want to ensure that supply chain and ESJ concerns are considered and integrated as part of decision making throughout the research and development process.

Background Patients experience atrial fibrillation (AF) as a complex disease given its adversity, chronicity, and necessity for long‐term treatments. Few studies have examined the experience of rural individuals with AF. We conducted qualitative assessments of patients with AF residing in rural, western Pennsylvania to identify barriers and facilitators to care. Methods and Results We conducted 8 semistructured virtual focus groups with 42 individuals living in rural western Pennsylvania using contextually tailored questions to assess participant perspectives. We inductively analyzed focus group transcripts using paragraph‐by‐paragraph and focused coding to identify themes with the qualitative description approach. We used Krippendorff α scoring to determine interreviewer reliability. We harnessed investigator triangulation to augment the reliability of our findings. We reached thematic saturation after coding 8 focus groups. Participants were 52.4% women, with a median age of 70.9 years (range, 54.5–82.0 years), and most were White race (92.9%). Participants identified medication costliness, invisibility of AF to others, and lack of emergent transportation as barriers to care. Participants described interpersonal support and use of technology as important for AF self‐care, and expressed ambivalence about how relationships with health care providers affected AF care. Conclusions Focus group participants described multiple social and structural barriers to care for AF. Our findings highlight the complexity of the experience of individuals with AF residing in rural western Pennsylvania. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT 04076020.

Abstract Background Nef performs multiple cellular activities that enhance HIV-1 pathogenesis. The role of Nef-mediated down-regulation of the host restriction factor SERINC5 in HIV-1 pathogenesis is not well-defined. We aimed to investigate if SERINC5 down-regulation activity contributes to HIV-1 subtype C disease progression, to assess the relative contribution of this activity to overall Nef function, and to identify amino acids required for optimal activity. We measured the SERINC5 down-regulation activity of 106 subtype C Nef clones, isolated from individuals in early infection, for which the Nef activities of CD4 and HLA-I down-regulation as well as alteration of TCR signalling were previously measured. The relationship between SERINC5 down-regulation and markers of disease progression, and the relative contribution of SERINC5 down-regulation to a Nef fitness model-derived E value (a proxy for overall Nef fitness in vivo), were assessed. Results No overall relationship was found between SERINC5 down-regulation and viral load set point (p = 0.28) or rate of CD4+ T cell decline (p = 0.45). CD4 down-regulation (p = 0.02) and SERINC5 down-regulation (p = 0.003) were significant determinants of E values in univariate analyses, with the greatest relative contribution for SERINC5 down-regulation, and only SERINC5 down-regulation remained significant in the multivariate analysis (p = 0.003). Using a codon-by-codon analysis, several amino acids were significantly associated with increased (10I, 11V, 38D, 51T, 65D, 101V, 188H and, 191H) or decreased (10K, 38E, 65E, 135F, 173T, 176T and, 191R) SERINC5 down-regulation activity. Site-directed mutagenesis experiments of selected mutants confirmed a substantial reduction in SERINC5 down-regulation activity associated with the mutation 173T, while mutations 10K, 135F, and 176T were associated with more modest reductions in activity that were not statistically significant. Conclusions These results suggest that SERINC5 down-regulation is a significant contributor to overall Nef function and identify potential genetic determinants of this Nef function that may have relevance for vaccines or therapeutics.

Summary: Monochorionic-diamniotic twin pregnancies are susceptible to unique complications arising from a single placenta shared by two fetuses. Twin-twin transfusion syndrome (TTTS) is a constellation of disturbances caused by unequal blood flow within the shared placenta giving rise to a major hemodynamic imbalance between the twins. Here, we applied TTTS as a model to uncover fetal metabolic adaptations to cardiovascular stress. We compared untargeted metabolomic analyses of amniotic fluid samples from severe TTTS cases vs. singleton controls. Amniotic fluid metabolites demonstrated alterations in fatty acid, glucose, and steroid hormone metabolism in TTTS. Among TTTS cases, unsupervised principal component analysis revealed two distinct clusters of disease defined by levels of glucose metabolites, amino acids, urea, and redox status. Our results suggest that the human fetal heart can adapt to hemodynamic stress by modulating its glucose metabolism and identify potential differences in the ability of individual fetuses to respond to cardiovascular stress.

Exposure to environmental pollutants is linked to increased risk of cardiovascular disease. Beyond the extensive evidence for particulate air pollution, accumulating evidence supports that exposure to nonessential metals such as lead, cadmium, and arsenic is a significant contributor to cardiovascular disease worldwide. Humans are exposed to metals through air, water, soil, and food and extensive industrial and public use. Contaminant metals interfere with critical intracellular reactions and functions leading to oxidative stress and chronic inflammation that result in endothelial dysfunction, hypertension, epigenetic dysregulation, dyslipidemia, and changes in myocardial excitation and contractile function. Lead, cadmium, and arsenic have been linked to subclinical atherosclerosis, coronary artery stenosis, and calcification as well as to increased risk of ischemic heart disease and stroke, left ventricular hypertrophy and heart failure, and peripheral artery disease. Epidemiological studies show that exposure to lead, cadmium, or arsenic is associated with cardiovascular death mostly attributable to ischemic heart disease. Public health measures reducing metal exposure are associated with reductions in cardiovascular disease death. Populations of color and low socioeconomic means are more commonly exposed to metals and therefore at greater risk of metal‐induced cardiovascular disease. Together with strengthening public health measures to prevent metal exposures, development of more sensitive and selective measurement modalities, clinical monitoring of metal exposures, and the development of metal chelation therapies could further diminish the burden of cardiovascular disease attributable to metal exposure.

Abstract Background Adequate housing is a basic human right. The many millions of people experiencing homelessness (PEH) have a lower life expectancy and more physical and mental health problems. Practical and effective interventions to provide appropriate housing are a public health priority. Objectives To summarise the best available evidence relating to the components of case‐management interventions for PEH via a mixed methods review that explored both the effectiveness of interventions and factors that may influence its impact. Search Methods We searched 10 bibliographic databases from 1990 to March 2021. We also included studies from Campbell Collaboration Evidence and Gap Maps and searched 28 web sites. Reference lists of included papers and systematic reviews were examined and experts contacted for additional studies. Selection Criteria We included all randomised and non‐randomised study designs exploring case management interventions where a comparison group was used. The primary outcome of interest was homelessness. Secondary outcomes included health, wellbeing, employment and costs. We also included all studies where data were collected on views and experiences that may impact on implementation. Data Collection and Analysis We assessed risk of bias using tools developed by the Campbell Collaboration. We conducted meta‐analyses of the intervention studies where possible and carried out a framework synthesis of a set of implementation studies identified by purposive sampling to represent the most ‘rich’ and ‘thick’ data. Main Results We included 64 intervention studies and 41 implementation studies. The evidence base was dominated by studies from the USA and Canada. Participants were largely (though not exclusively) people who were literally homeless, that is, living on the streets or in shelters, and who had additional support needs. Many studies were assessed as having a medium or high risk of bias. However, there was some consistency in outcomes across studies that improved confidence in the main findings. Case Management and Housing Outcomes Case management of any description was superior to usual care for homelessness outcomes (standardised mean difference [SMD] = −0.51 [95% confidence interval [CI]: −0.71, −0.30]; p 3 years) (SMD = −0.64 [−1.04, −0.24] vs. −0.27 [−0.53, 0]; p = 0.16) and for in‐person meetings in comparison to mixed (in‐person and remote) approaches (SMD = −0.73 [−1.25,−0.21]) versus −0.26 [−0.5,−0.02]; p = 0.13). There was no evidence from meta‐analyses to suggest that an individual case manager led to better outcomes then a team, and interventions with no dedicated case manager may have better outcomes than those with a named case manager (SMD = −0.36 [−0.55, −0.18] vs. −1.00 [−2.00, 0.00]; p = 0.02). There was not enough evidence from meta‐analysis to assess whether the case manager should have a professional qualification, or if frequency of contact, case manager availability or conditionality (barriers due to conditions attached to service provision) influenced outcomes. However, the main theme from implementation studies concerned barriers where conditions were attached to services. Characteristics of Persons Experiencing Homelessness No conclusions could be drawn from meta‐analysis other than a trend for greater reductions in homelessness for persons with high complexity of need (two or more support needs in addition to homelessness) as compared to those with medium complexity of need (one additional support need); effect sizes were SMD = −0.61 [−0.91, −0.31] versus −0.36 [−0.68, −0.05]; p = 0.3. The Broader Context of Delivery of Case Management Programmes Other major themes from the implementation studies included the importance of interagency partnership; provision for non‐housing support and training needs of PEH (such as independent living skills), intensive community support following the move to new housing; emotional support and training needs of case managers; and an emphasis on housing safety, security and choice. Cost Effectiveness The 12 studies with cost data provided contrasting results and no clear conclusions. Some case management costs may be largely off‐set by reductions in the use of other services. Cost estimates from three North American studies were $45–52 for each additional day housed. Authors' Conclusions Case management interventions improve housing outcomes for PEH with one or more additional support needs, with more intense interventions leading to greater benefits. Those with greater support needs may gain greater benefit. There is also evidence for improvements to capabilities and wellbeing. Current approaches do not appear to lead to mental health benefits. In terms of case management components, there is evidence in support of a team approach and in‐person meetings and, from the implementation evidence, that conditions associated with service provision should be minimised. The approach within Housing First could explain the finding that overall benefits may be greater than for other types of case management. Four of its principles were identified as key themes within the implementation studies: No conditionality, offer choice, provide an individualised approach and support community building. Recommendations for further research include an expansion of the research base outside North America and further exploration of case management components and intervention cost‐effectiveness.

Introduction: Access to a full range of contraceptive services is essential for quality health care. Contraceptive provision practices of primary care providers play an important role in patients' decision-making about their reproductive health care. Understanding the multilevel factors influencing contraceptive care delivery in primary care settings is critical for advancing quality care. This study offers an in-depth examination of influences on providers' delivery of contraceptive services across multiple primary care specialties and practice settings to identify issues and strategies to improve care. Materials and Methods: Twenty-four in-depth face-to-face interviews were conducted in 2017 with primary care providers, including family physicians, gynecologists, pediatricians, and nurse practitioners from academic settings, private practices, and health centers. Interviews were transcribed and analyzed thematically. Results: Providers described a complex set of influences on their provision of contraception across multiple ecological contexts. Seven major themes emerged from the qualitative analysis, including six types of influence on provision of contraception: organizational, individual provider-related, structural and policy, individual patient-related, community, and the lack of influences or barriers. Providers also discussed the sources they access for information about evidence-based contraception counseling. Conclusions: A diverse set of providers described a complex system in which multiple concentric ecological contexts both positively and negatively influence the ways in which they provide contraceptive services to their patients. To close the gaps in contraceptive service delivery, it is important to recognize that both barriers and facilitators to patient-centered contraceptive counseling exist simultaneously across multiple ecological contexts.

Khan et al. use human blood and a macaque model of tuberculosis (TB) to assess whether macrophage heterogeneity contributes to TB immunity. They demonstrate that human macrophages show unique patterns of gene expression that enable differential control of TB after infection.

Abstract Diffuse large B cell lymphoma (DLBCL) is successfully treated with combination immuno-chemotherapy, but relapse with resistant disease occurs in ~ 40% of patients. However, little is known regarding relapsed/refractory DLBCL (rrDLBCL) genetics and alternative therapies. Based on findings from other tumors, we hypothesized that RAS-MEK-ERK signaling would be upregulated in resistant tumors, potentially correlating with mutations in RAS, RAF, or associated proteins. We analyzed mutations and phospho-ERK levels in tumor samples from rrDLBCL patients. Unlike other tumor types, rrDLBCL is not mutated in any Ras or Raf family members, despite having increased expression of p-ERK. In paired biopsies comparing diagnostic and relapsed specimens, 33% of tumors gained p-ERK expression, suggesting a role in promoting survival. We did find mutations in several Ras-associating proteins, including GEFs, GAPs, and downstream effectors that could account for increased ERK activation. We further investigated mutations in one such protein, RASGRP4. In silico modeling indicated an increased interaction between H-Ras and mutant RASGRP4. In cell lines, mutant RASGRP4 increased basal p-ERK expression and lead to a growth advantage in colony forming assays when challenged with doxorubicin. Relapsed/refractory DLBCL is often associated with increased survival signals downstream of ERK, potentially corresponding with mutations in protein controlling RAS/MEK/ERK signaling.

Previous work suggests that HIV controllers with protective human leukocyte antigen class I alleles (VC+) possess a high breadth of Gag-specific CD8+ T cell responses, while controllers without protective alleles (VC-) have a different unknown mechanism of control. We aimed to gain further insight into potential mechanisms of control in VC+ and VC-. We studied 15 VC+, 12 VC- and 4 healthy uninfected individuals (UI). CD8+ T cell responses were measured by ELISpot. Flow cytometry was performed to analyse surface markers for activation, maturation, and exhaustion on natural killer (NK) cell and T cells, as well as cytokine secretion from stimulated NK cells. We measured plasma neutralization activity against a panel of 18 Env-pseudotyped viruses using the TZM-bl neutralization assay. We found no significant differences in the magnitude and breadth of CD8+ T cell responses between VC+ and VC-. However, NK cells from VC- had higher levels of activation markers (HLA-DR and CD38) (p = 0.03), and lower cytokine expression (MIP-1β and TNF-α) (p = 0.05 and p = 0.04, respectively) than NK cells from VC+. T cells from VC- had higher levels of activation (CD38 and HLA-DR co-expression) (p = 0.05), as well as a trend towards higher expression of the terminal differentiation marker CD57 (p = 0.09) when compared to VC+. There was no difference in overall neutralization breadth between VC+ and VC- groups, although there was a trend for higher neutralization potency in the VC- group (p = 0.09). Altogether, these results suggest that VC- have a more activated NK cell profile with lower cytokine expression, and a more terminally differentiated and activated T cell profile than VC+. VC- also showed a trend of more potent neutralizing antibody responses that may enhance viral clearance. Further studies are required to understand how these NK, T cell and antibody profiles may contribute to differing mechanisms of control in VC+ and VC-.

Pleuropulmonary blastoma is a rare and highly aggressive pulmonary malignancy in children. Clinically, the malignancy is often mistaken for symptoms of respiratory tract infection or pneumothorax. The neoplasm is histologically characterized by primitive blastema and a malignant mesenchymal stroma that demonstrates multidirectional differentiation. The patients with PPB are managed by multimodal therapy. We present a report of 3 cases of histopathologically diagnosed pleuropulmonary blastoma. The patients presented with chief complaints of difficulty in breathing, cough, fever and chest pain. Radiographs of the patients showed partial to complete opacification of hemithorax. Contrast enhanced computed tomography scans revealed large well defined heterogenously enhancing solid mass lesions in the hemithorax. Knowledge of types, imaging findings, staging and association with other tumors is crucial for correct diagnosis of pleuropulmonary blastoma and subsequent adequate management.

Failure to properly form bone or integrate surgical implants can lead to morbidity and additional surgical interventions in a significant proportion of orthopedic surgeries. While the role of skeletal stem cells (SSCs) in bone formation and repair is well-established, very little is known about the factors that regulate the downstream Bone, Cartilage, Stromal, Progenitors (BCSPs). BCSPs, as transit amplifying progenitor cells, undergo multiple mitotic divisions to expand the pool of lineage committed progenitors allowing stem cells to preserve their self-renewal and stemness. Del1 is a protein widely expressed in the skeletal system, but its deletion led to minimal phenotype changes in the uninjured mouse. In this paper, we demonstrate that Del1 is a key regulator of BCSP expansion following injury. In Del1 knockout mice, there is a significant reduction in the number of BCSPs which leads to a smaller callus and decreased bone formation compared with wildtype (WT) littermates. Del1 serves to promote BCSP proliferation and prevent apoptosis in vivo and in vitro. Moreover, exogenous Del1 promotes proliferation of aged human BCSPs. Our results highlight the potential of Del1 as a therapeutic target for improving bone formation and implant success. Del1 injections may improve the success of orthopedic surgeries and fracture healing by enhancing the proliferation and survival of BCSPs, which are crucial for generating new bone tissue during the process of bone formation and repair.

Abstract Background This study evaluates the role of social isolation on inflammation and cancer mortality among women. Methods Data were abstracted from the U.S. National Health and Nutrition Examination Survey from 1988 to 1994. The Social Network Index was used to assess participants’ degree of social isolation. C-reactive protein and fibrinogen levels were included as markers of inflammation. We used the National Death Index to identify causes and dates of mortality. Chi-square and multivariable Cox regressions were employed for statistical analyses. Results Of 3360 women (median age: 54 years), the most isolated, very isolated, somewhat isolated, and not isolated comprised 14.5, 30.2, 37.1, and 18.2% of the sample, respectively. The most isolated participants were more likely to have low income (56.8% vs 12.2%, p

The Integrated Stress Response (ISR) is a cytoprotective pathway upregulated in many cancers. Here the authors show that the activation of PERK/p-eIF2α arm of ISR enhances ERK phosphorylation through translation repression of DUSP6, thus resulting in KRAS-driven lung tumorigenesis.

BackgroundAmong women in the United States, cancer is the second leading cause of death. Prior studies have examined how lifestyle factors, such as diet and physical activity, influence cancer mortality. However, few have evaluated if diet or physical activity has a stronger protective effect for cancer mortality. Therefore, this study aims to evaluate and compare the impacts of diet and physical activity on women's cancer mortality.MethodsProspective, cross-sectional data were abstracted from the Third US National Health and Nutrition Examination Survey (NHANES III) on female respondents from 1988 to 1994. Physical activity was derived from the CDC's metabolic equivalent (MET) intensity levels. Dietary classifications were derived from the USDA's healthy eating index (HEI). We utilized the National Death Index to obtain mortality follow-up information on our cohort until December 31, 2015. Chi-squared, multivariable Cox regression, and Kaplan–Meier estimates were employed for statistical analyses.ResultsOf 3,590 women (median age: 57, range: 40–89), 30% had an obese BMI (BMI≥30 kg/m2). Additionally, 22% of participants self-reported a healthy diet, 69% needed dietary improvement, and 9% had a poor diet. Furthermore, 21% reported physical inactivity, 44% did not meet physical activity guidelines, and 35% met guidelines. On multivariate analysis, healthy diet (HR: 0.70; 95% CI: 0.51–0.98; p = 0.04), but not physical activity (HR: 0.87; 95% CI: 0.55–1.38; p = 0.55), independently predicted for lower cancer mortality. Participants with a healthy diet but low exercise had decreased cancer mortality compared to participants with an unhealthy diet but high exercise (p = 0.01).ConclusionsA healthful diet was associated with lower cancer mortality in women, even after adjusting for obesity, inflammation, and other covariates. In addition, diet may play a stronger role in reducing cancer mortality in women than physical activity.

HIV variants present in the reservoir, particularly in tissues, may differ from those present in peripheral blood prior to therapy initiation, and characterisation of these reservoir variants could better inform immune-based interventions for HIV cure. In the present study, Gag sequence differences between variants derived from the lymph node and peripheral blood mononuclear cell (PBMC) reservoirs as well as those derived from pre-therapy plasma, were investigated in 24 HIV-1 subtype C-infected individuals. HIV gag amplification was successful for 20 individuals, where 4 were controls including one untreated individual and 3 early treated individuals with LN collection within 2 weeks of treatment initiation. The remaining 16 individuals with LN and PBMC collection > 3 months after treatment initiation (median = 665 days), were further characterised. Recombinant viruses encoding patient-derived Gag-protease sequences from the pre-therapy plasma, LN reservoir, and PBMC reservoir, were constructed and the replication-competent viruses that grew in vitro were used to further investigate whether there are specific features of Gag reservoir variants that may have relevance for strategies to cure HIV. Virus characteristics measured included replication capacity, interferon-alpha resistance, cell-to-cell spread ability, and induction of antiviral cytokines. A limited number of novel Gag mutations (median = 4) in the reservoir of 3/7 early treated participants and 9/9 late treated participants were observed, where the majority of these mutations were likely cytotoxic T lymphocyte (CTL)-driven and 48% were represented in the replication-competent viruses. The reservoir variants had very few unique potential CTL escape mutations (median = 3) in Gag compared to the number of these Gag mutations that were already present in the plasma-derived virus (median = 23) at the time of treatment initiation, which was similar whether treatment was initiated late or early. The data suggest that the extent of CTL escape in Gag overall is likely similar between early and late treated individuals as well as between the reservoir and pre-therapy variants. The sequence differences in Gag that were unique to the reservoir viruses did not result in significantly altered virus characteristics overall, and are therefore unlikely to affect effectiveness of immune-based interventions for virus eradication.

Abstract Background The HIV-1 epidemic in sub-Saharan Africa is heterogeneous with diverse unevenly distributed subtypes and regional differences in prevalence. Subtype-specific differences in disease progression rate and transmission efficiency have been reported, but the underlying biological mechanisms have not been fully characterized. Here, we tested the hypothesis that the subtypes prevalent in the East Africa, where adult prevalence rate is higher, have lower viral replication capacity (VRC) than their West African counterparts where adult prevalence rates are lower. Results Gag-protease sequencing was performed on 213 and 160 antiretroviral-naïve chronically infected participants from West and East Africa respectively and bioinformatic tools were used to infer subtypes and recombination patterns. VRC of patient-derived gag-protease chimeric viruses from West (n = 178) and East (n = 114) Africa were determined using a green fluorescent protein reporter-based cell assay. Subtype and regional differences in VRC and amino acid variants impacting VRC were identified by statistical methods. CRF02_AG (65%, n = 139), other recombinants (14%, n = 30) and pure subtypes (21%, n = 44) were identified in West Africa. Subtypes A1 (64%, n = 103), D (22%, n = 35), or recombinants (14%, n = 22) were identified in East Africa. Viruses from West Africa had significantly higher VRC compared to those from East Africa (p

HIV-1 accessory proteins Nef and Vpu enhance viral pathogenesis through partially overlapping immune evasion activities. Attenuated Nef or Vpu functions have been reported in individuals who display slower disease progression, but few studies have assessed the relative impact of these proteins in non-B HIV-1 subtypes or examined paired proteins from the same individuals. Here, we examined the sequence and function of matched Nef and Vpu clones isolated from 29 long-term survivors (LTS) from Rwanda living with HIV-1 subtype A and compared our results to those of 104 Nef and 62 Vpu clones isolated from individuals living with chronic untreated HIV-1 subtype A from the same geographic area. Nef and vpu coding regions were amplified from plasma HIV RNA and cloned. The function of one intact, phylogenetically-validated Nef and Vpu clone per individual was then quantified by flow cytometry following transient expression in an immortalized CD4+ T-cell line. We measured the ability of each Nef clone to downregulate CD4 and HLA class I, and of each Vpu clone to downregulate CD4 and Tetherin, from the cell surface. Results were normalized to reference clones (Nef-SF2 and Vpu-NL4.3). We observed that Nef-mediated CD4 and HLA downregulation functions were lower in LTS compared to the control cohort (Mann-Whitney p=0.03 and p

Abstract Background To estimate the relationship between inflammatory biomarkers and cancer mortality in a nationally representative sample of the U.S. population while controlling for education, occupation, and income. Methods Data were obtained from the U.S. National Health and Nutrition Examination Survey from 1988 to 1994 (N = 7817) and 1999–2002 (N = 2344). We fit Cox proportional hazard models to examine the relationship between C-reactive protein (CRP) and fibrinogen with cancer mortality. Results In the full Cox multivariate model, clinically raised CRP was associated with cancer mortality in NHANES 1988–1994 (> 0.99 mg/dL: 95%CI: 1.04–2.13). However, across two inflammatory biomarkers (CRP and Fibrinogen), two NHANES time periods (1998–1994 and 1999–2002) and three income levels (12 strata in total), Hazard ratio confidence intervals did not include the null only for one association: CRP and cancer mortality among low income participants from 1988 to 1994 (HR = 1.83, 95% CI: 1.10–3.04). Conclusions We find evidence that only in one unique stratum is earlier life CRP, and not fibrinogen, associated with prospective cancer mortality. After more complete control for socioeconomic confounding, CRP and fibrinogen do not predict cancer mortality in most subpopulations.

Abstract Introduction Immunological damage in acute HIV infection (AHI) may predispose to detrimental clinical sequela. However, studies on the earliest HIV-induced immunological changes are limited, particularly in sub-Saharan Africa. We assessed the plasma cytokines kinetics, and their associations with virological and immunological parameters, in a well-characterized AHI cohort where participants were diagnosed before peak viremia. Methods Blood cytokine levels were measured using Luminex and ELISA assays pre-infection, during the hyperacute infection phase (before or at peak viremia, 1–11 days after the first detection of viremia), after peak viremia (24–32 days), and during the early chronic phase (77–263 days). Gag-protease-driven replicative capacities of the transmitted/founder viruses were determined using a green fluorescent reporter T cell assay. Complete blood counts were determined before and immediately following AHI detection before ART initiation. Results Untreated AHI was associated with a cytokine storm of 12 out of the 33 cytokines analyzed. Initiation of ART during Fiebig stages I–II abrogated the cytokine storm. In untreated AHI, virus replicative capacity correlated positively with IP-10 (rho = 0.84, P

Abstract This is the protocol for a Campbell review. The objectives are as follows: To carry out a mixed methods review to summarise current evidence relating to the components of case‐management interventions for people experiencing homelessness.

The COVID-19 pandemic prompted faculty across the country to pivot their in-person courses to ones that could be offered virtually. Some faculty learned quickly that our economically-challenged students had difficulty trying to access resources that suddenly became remote. In this reflective article, we will highlight the experiences of five social scientists’ efforts to transform courses from in-person to remote delivery, attending to each of the “presences” in the Community of Inquiry (COI) framework (Garrison, Anderson, & Archer, 2001), while also addressing the economic challenges of students on a regional mid-western campus. We end with several “lessons learned” and suggestions for remote delivery as we move forward. Keywords: Community of Inquiry, online learning, social science

HIV Nef counteracts cellular host restriction factors SERINC3 and SERINC5, but our understanding of how naturally occurring global Nef sequence diversity impacts these activities is limited. Here, we quantify SERINC3 and SERINC5 internalization function for 339 Nef clones, representing the major pandemic HIV-1 group M subtypes A, B, C and D. We describe distinct subtype-associated hierarchies for Nef-mediated internalization of SERINC5, for which subtype B clones display the highest activities on average, and of SERINC3, for which subtype B clones display the lowest activities on average. We further identify Nef polymorphisms that modulate its ability to counteract SERINC proteins, including substitutions in the N-terminal domain that selectively impair SERINC3 internalization. Our findings demonstrate that the SERINC antagonism activities of HIV Nef differ markedly among major viral subtypes and between individual isolates within a subtype, suggesting that variation in these functions may contribute to global differences in viral pathogenesis.

Background. Cocaine use is associated with multiple cardiovascular complications including heart failure. The use of different types of beta blockers in heart failure patients with active cocaine use is still a matter of debate. In this review, our objective is to systematically review the available literature regarding the use of beta blockers in the treatment of heart failure patients with concurrent cocaine use. Methods. PubMed, EMBASE, Web of Science, and Clinical Trials.gov were searched from inception to March 2019 using the Medical Subject Headings (MeSH) terms “cocaine”, “heart failure”, “beta blocker,” and “cardiomyopathy”. Only studies containing the outcomes of heart failure patients with active cocaine use who were treated with beta blockers were included. Results. The search resulted in 2072 articles out of which 12 were finally included in the review. A total number of participants were 1994 with a median sample size of 111. Most of the studies were retrospective in nature with Oxford Centre for Evidence-Based Medicine (OCEBM) Levels of Evidence from 3 to 5. The main primary outcomes included readmission rates, mortality, left ventricular ejection fraction (LVEF) improvement, New York Heart Association (NYHA) functional class, and major adverse cardiovascular events (MACEs). In the studies analyzed, beta blockers were found to have either a beneficial or a neutral effect on primary outcomes in heart failure patients with active cocaine use. Conclusion. The use of beta blocker therapy appears to be safe and beneficial in heart failure patients with active cocaine use, although the evidence is not robust. Furthermore, large-scale studies are required to confirm this finding.

Introduction. South Asians in the United States have a high prevalence of obesity and an elevated risk for cardiometabolic diseases. Yet, little is known about how aspects of neighborhood environment influence cardiometabolic risk factors such as body mass index (BMI) in this rapidly growing population. We aimed to investigate the association between perceived neighborhood social cohesion and BMI among South Asians. Methods. We utilized cross-sectional data from the MASALA study, a prospective community-based cohort of 906 South Asian men and women from the San Francisco Bay area and the greater Chicago area. Multivariable linear regression models, stratified by sex, were used to examine the association between perceived level of neighborhood social cohesion and individual BMI after adjusting for sociodemographics. Results. Participants were 54% male, with an average age of 55 years, 88% had at least a bachelor’s degree, and the average BMI was 26.0 kg/m2. South Asian women living in neighborhoods with the lowest social cohesion had a significantly higher BMI than women living in neighborhoods with the highest cohesion (β coefficient = 1.48, 95% CI 0.46–2.51, p=0.02); however, the association was not statistically significant after adjusting for sociodemographic factors (β coefficient = 1.06, 95% CI −0.01–2.13, p=0.05). There was no association between level of neighborhood social cohesion and BMI in South Asian men. Conclusion. Perceived neighborhood social cohesion was not significantly associated with BMI among South Asians in our study sample. Further research is recommended to explore whether other neighborhood characteristics may be associated with BMI and other health outcomes in South Asians and the mechanisms through which neighborhood may influence health.

Despite the proven clinical antineoplastic activity of histone deacetylase inhibitors (HDACI), their effect has been reported to be lower than expected in B-cell lymphomas. Traditionally considered as “epigenetic drugs”, HDACI modify the acetylation status of an extensive proteome, acting as general lysine deacetylase inhibitors (KDACI), and thus potentially impacting various branches of cellular metabolism. Here, we demonstrate through metabolomic profiling of patient plasma and cell lines that the KDACI panobinostat alters lipid metabolism and downstream survival signaling in diffuse large B-cell lymphomas (DLBCL). Specifically, panobinostat induces metabolic adaptations resulting in newly acquired dependency on the choline pathway and activation of PI3K signaling. This metabolic reprogramming decreased the antineoplastic effect of panobinostat. Conversely, inhibition of these metabolic adaptations resulted in superior anti-lymphoma effect as demonstrated by the combination of panobinostat with a choline pathway inhibitor. In conclusion, our study demonstrates the power of metabolomics in identifying unknown effects of KDACI, and emphasizes the need for a better understanding of these drugs in order to achieve successful clinical implementation.

Analysis by attenuated total reflection–Fourier transform infrared spectroscopy shows that each coexisting phase in aqueous two-phase systems has a different arrangement of hydrogen bonds. Specific arrangements vary for systems formed by different solutes. The hydrogen bond arrangement is shown to correlate with differences in hydrophobic and electrostatic properties of the different phases of five specific systems, four formed by two polymers and one by a single polymer and salt. The results presented here suggest that the arrangement of hydrogen bonds may be an important factor in phase separation.

Abstract Nematic liquid crystals (NLCs) of achiral molecules and racemic mixtures of chiral ones form flat films and show uniform textures between circular polarizers when suspended in sub-millimeter size grids and immersed in water. On addition of chiral dopants to the liquid crystal, the films exhibit optical textures with concentric ring patterns and radial variation of the birefringence color. Both are related to a biconvex shape of the chiral liquid crystal film; the rings are due to interference. The curvature radii of the biconvex lens array are in the range of a few millimeters. This curvature leads to a radial variation of the optical axis along the plane of the film. Such a Pancharatnam-type phase lens dominates the imaging and explains the measured focal length of about one millimeter. To our knowledge, these are the first spontaneously formed Pancharatnam devices. The unwinding of the helical structure at the grid walls drives the lens shape. The relation between the lens curvature and material properties such as helical pitch, the twist elastic constant, and the interfacial tensions, is derived. This simple, novel method for spontaneously forming microlens arrays can also be used for various sensors.

Tyrosine kinase signalling in cancer cells promotes immune evasion. Here, the authors show that tyrosine kinases engage scaffold protein Shc1 to promote immunosuppression in breast cancer by simultaneously activating STAT3 immunosuppressive signals and impairing STAT1-driven anti-tumour immune responses.

Satellite telemetry is an increasingly utilized technology in wildlife research, and current devices can track individual animal movements at unprecedented spatial and temporal resolutions. However, as we enter the golden age of satellite telemetry, we need an in-depth understanding of the main technological, species-specific and environmental factors that determine the success and failure of satellite tracking devices across species and habitats. Here, we assess the relative influence of such factors on the ability of satellite telemetry units to provide the expected amount and quality of data by analyzing data from over 3,000 devices deployed on 62 terrestrial species in 167 projects worldwide. We evaluate the success rate in obtaining GPS fixes as well as in transferring these fixes to the user and we evaluate failure rates. Average fix success and data transfer rates were high and were generally better predicted by species and unit characteristics, while environmental characteristics influenced the variability of performance. However, 48% of the unit deployments ended prematurely, half of them due to technical failure. Nonetheless, this study shows that the performance of satellite telemetry applications has shown improvements over time, and based on our findings, we provide further recommendations for both users and manufacturers.