Intra-tumoral and peripheral blood TIGIT and PD-1 as immune biomarkers in nodular lymphocyte predominant Hodgkin lymphoma.

In classical Hodgkin lymphoma (cHL), responsiveness to immune-checkpoint blockade (ICB) is associated with specific tumor microenvironment (TME) and peripheral blood features. The role of ICB in nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is not established. To gain insights into its potential in NLPHL, we compared TME and peripheral blood signatures between HLs using an integrative multiomic analysis. A discovery/validation approach in 121 NLPHL and 114 cHL patients highlighted >2-fold enrichment in programmed cell death-1 (PD-1) and T-cell Ig and ITIM domain (TIGIT) gene expression for NLPHL versus cHL. Multiplex imaging showed marked increase in intra-tumoral protein expression of PD-1+ (and/or TIGIT+) CD4+ T-cells and PD-1+CD8+ T-cells in NLPHL compared to cHL. This included T-cells that rosetted with lymphocyte predominant (LP) and Hodgkin Reed-Sternberg (HRS) cells. In NLPHL, intra-tumoral PD-1+CD4+ T-cells frequently expressed TCF-1, a marker of heightened T-cell response to ICB. The peripheral blood signatures between HLs were also distinct, with higher levels of PD-1+TIGIT+ in TH1, TH2, and regulatory CD4+ T-cells in NLPHL versus cHL. Circulating PD-1+CD4+ had high levels of TCF-1. Notably, in both lymphomas, highly expanded populations of clonal TIGIT+PD-1+CD4+ and TIGIT+PD-1+CD8+ T-cells in the blood were also present in the TME, indicating that immune-checkpoint expressing T-cells circulated between intra-tumoral and blood compartments. In in vitro assays, ICB was capable of reducing rosette formation around LP and HRS cells, suggesting that disruption of rosetting may be a mechanism of action of ICB in HL. Overall, results indicate that further evaluation of ICB is warranted in NLPHL.

Keeping it real: A descriptive analysis of HIV testing history, PrEP awareness, and PrEP use among Black cisgender women in Middle Tennessee, 2018.

INTRODUCTION: HIV disproportionately affects Black/African American women in the United States, particularly in the southern states, including Tennessee. Despite this, limited research and intervention are targeting this population, especially regarding biomedical prevention technologies such as pre-exposure prophylaxis (PrEP). This study aims to describe the HIV testing history of a sample of Black women in middle Tennessee, assess their awareness and potential for adopting modern HIV prevention technologies like PrEP, and explore the dyadic and social factors that influence their HIV prevention awareness and use. THEORY: The Precaution Adoption Process Model (PAPM) is employed to understand how individuals progress through decision-making stages when adopting new health behaviors, especially related to novel interventions. METHODS: For survey development and deployment, this cross-sectional survey study engaged the Nashville Health Disparities Coalition and the Resident Association for the Metropolitan Developmental Housing Association in Nashville. Eligible participants included African American and Black women aged 18 and above. The survey collected demographic information, HIV testing history, reasons for testing or not testing, dyadic HIV risk factors, awareness, and use of rapid HIV testing and PrEP, and social norms related to these prevention technologies. RESULTS AND DISCUSSION: Age significantly influenced HIV testing history, emphasizing the importance of regular screening, especially among older women. Dyadic factors such as concurrency and having a shared male partner were associated with differences in testing behavior. Awareness of both rapid HIV testing and PrEP was limited among participants, highlighting the need for increased education and awareness campaigns specifically highlighting benefits to Black women. Social norms, particularly recommendations from healthcare providers, played a crucial role in influencing women's willingness to adopt these prevention technologies. [Increasing routine HIV testing and awareness of PrEP, especially among women in non-monogamous relationships, is essential in reducing HIV disparities among Black women.] IMPLICATIONS: Healthcare providers play a crucial role in initiating and recommending HIV testing and PrEP among Black women, emphasizing the importance of patient-provider relationships and ongoing conversations about prevention strategies. This study underscores the importance of community-engaged research in addressing HIV disparities and highlights the potential for partnerships between medical centers and community organizations in the fight against HIV.

Varicella-Zoster Virus Pretransplant Vaccination and Posttransplant Infections Among Pediatric Solid Organ Recipients in the Two-Dose Varicella Era: A Single-Center, Multi-Organ Retrospective Study.

BACKGROUND: Varicella-zoster virus (VZV) pretransplant immunization rates, exposures, and posttransplant disease are poorly characterized among pediatric solid organ transplant (SOT) recipients in the two-dose varicella vaccine era. METHODS: A retrospective analysis of the electronic health records among children <18 years old who received SOT from January 1, 2011 through December 31, 2021, was performed at a single center to assess for missed pretransplant varicella vaccination opportunities, characterize VZV exposures, and describe posttransplant disease. RESULTS: Among 525 children, 444 were ≥6 months old (m.o.) at SOT with a documented VZV vaccine status. Eighty-five (19%) did not receive VZV Dose One; 30 out of 85 (35%) could have been immunized. Infants 6-11 m.o. accounted for 14 out of 30 (47%) missed opportunities. Among children ≥12 m.o. with documented Dose Two status (n = 383), 72 had missed vaccination opportunities; 57 out of 72 (79%) were children 1-4 years old. Most children had unclassifiable pre-SOT serostatus as varicella serology was either not obtained/documented (n = 171) or the possibility of passive antibodies was not excluded (n = 137). Of those with classified serology (n = 188), 69 were seroimmune. Forty-seven of 525 (9%) children had recorded VZV exposures; two developed varicella-neither had documented pre-SOT seroimmunity nor had received post-exposure prophylaxis. Nine additional children had medically attended disease: four primary varicella and five zoster. Of the 11 cases, 10 had cutaneous lesions without invasive disease; one had multi-dermatomal zoster with transaminitis. Seven (64%) received treatment exclusively outpatient. CONCLUSIONS: VZV exposure and disease still occur. Optimizing immunization among eligible candidates and ensuring patients have a defined VZV serostatus pretransplantation remain goals of care.

A double ovulation protocol for Xenopus laevis produces doubled fertilisation yield and moderately transiently elevated corticosterone levels without loss of egg quality.

The African claw-toed frog, Xenopus laevis, is a well-established laboratory model for the biology of vertebrate oogenesis, fertilisation, and development at embryonic, larval, and metamorphic stages. For ovulation, X. laevis females are usually injected with chorionic gonadotropin, whereupon they lay typically hundreds to thousands of eggs in a day. After being rested for a minimum of three months, animals are re-used. The literature suggests that adult females can lay much larger numbers of eggs in a short period. Here, we compared the standard "single ovulation" protocol with a "double ovulation" protocol, in which females were ovulated, then re-ovulated after seven days and then rested for three months before re-use. We quantified egg number, fertilisation rate (development to cleavage stage), and corticosterone secretion rate as a measure of stress response for the two protocol groups over seven 3-month cycles. We found no differences in egg number-per-ovulation or egg quality between the groups and no long-term changes in any measures over the 21-month trial period. Corticosterone secretion was elevated by ovulation, similarly for the single ovulation as for the first ovulation in the double-ovulation protocol, but more highly for the second ovulation (to a level comparable to that seen following shipment) in the latter. However, both groups exhibited the same baseline secretion rates by the time of the subsequent cycle. Double ovulation is thus transiently more stressful/demanding than single ovulation but within the levels routinely experienced by laboratory X. laevis. Noting that "stress hormone" corticosterone/cortisol secretion is linked to physiological processes, such as ovulation, that are not necessarily harmful to the individual, we suggest that the benefits of a doubling in egg yield-per-cycle per animal without loss of egg quality or signs of acute or long-term harm may outweigh the relatively modest and transient corticosterone elevation we observed. The double ovulation protocol therefore represents a potential new standard practice for promoting the "3Rs" (animal use reduction, refinement and replacement) mission for Xenopus research.

Topical and Subcutaneous Interferon-Alpha for the Treatment of Refractory Inflammatory Macular Edema.

PURPOSE: To evaluate the efficacy of topical interferon alpha-2b (tIFN a2b) and subcutaneous pegylated interferon alpha-2a (peg-IFN a2a) in the treatment of refractory pseudophakic (PME) and uveitic (UME) macular edema. METHODS: Retrospective case series of patients with PME or UME that was non-responsive to conventional therapies. Topical IFN a2b drops (1 MIU/ml) were commenced four times a day. Non-responders were offered treatment with subcutaneous peg-IFN a2a starting at 180 mcg weekly. RESULTS: Seven eyes of seven patients (three UME and four PME) were treated with tIFN a2b. Three eyes had complete ME resolution with tIFN treatment after a mean of 2.66 weeks (range 1-4 weeks) and no recurrence after a mean total course of 11.33 weeks (range 5-20 weeks). Two cases (both PME) had partial responses to tIFN treatment and two cases (both UME) failed to respond. Of the four eyes that incompletely responded to tIFN (treatment range 6 weeks to 4 months), three were treated with peg-IFN a2a, which invariably led to complete and sustained ME resolution. Adverse effects from topical treatment were mild and consisted mainly of superficial irritation. Adverse effects of subcutaneous treatment included nausea, vomiting, anorexia, and leukopenia, though none limited treatment. CONCLUSIONS: Topical IFNa-2b appears safe and effective in isolation or in conjunction with topical steroids for the treatment of inflammatory macular edema (IME) in about half of patients in our small series. All partial and non-responders had complete disease resolution with systemic IFN. Topical IFN a2b should be considered in patients with refractory IME.

Pain Reduction With Oral Methotrexate in Knee Osteoarthritis : A Randomized, Placebo-Controlled Clinical Trial.

BACKGROUND: Treatments for osteoarthritis (OA) are limited. Previous small studies suggest that the antirheumatic drug methotrexate may be a potential treatment for OA pain. OBJECTIVE: To assess symptomatic benefits of methotrexate in knee OA (KOA). DESIGN: A multicenter, randomized, double-blind, placebo-controlled trial done between 13 June 2014 and 13 October 2017. (ISRCTN77854383; EudraCT: 2013-001689-41). SETTING: 15 secondary care musculoskeletal clinics in the United Kingdom. PARTICIPANTS: A total of 207 participants with symptomatic, radiographic KOA and knee pain (severity ≥4 out of 10) on most days in the past 3 months with inadequate response to current medication were approached for inclusion. INTERVENTION: Participants were randomly assigned 1:1 to oral methotrexate once weekly (6-week escalation 10 to 25 mg) or matched placebo over 12 months and continued usual analgesia. MEASUREMENTS: The primary end point was average knee pain (numerical rating scale [NRS] 0 to 10) at 6 months, with 12-month follow-up to assess longer-term response. Secondary end points included knee stiffness and function outcomes and adverse events (AEs). RESULTS: A total of 155 participants (64% women; mean age, 60.9 years; 50% Kellgren-Lawrence grade 3 to 4) were randomly assigned to methotrexate (n = 77) or placebo (n = 78). Follow-up was 86% (n = 134; methotrexate: 66, placebo: 68) at 6 months. Mean knee pain decreased from 6.4 (SD, 1.80) at baseline to 5.1 (SD, 2.32) at 6 months in the methotrexate group and from 6.8 (SD, 1.62) to 6.2 (SD, 2.30) in the placebo group. The primary intention-to-treat analysis showed a statistically significant pain reduction of 0.79 NRS points in favor of methotrexate (95% CI, 0.08 to 1.51; P = 0.030). There were also statistically significant treatment group differences in favor of methotrexate at 6 months for Western Ontario and McMaster Universities Osteoarthritis Index stiffness (0.60 points [CI, 0.01 to 1.18]; P = 0.045) and function (5.01 points [CI, 1.29 to 8.74]; P = 0.008). Treatment adherence analysis supported a dose-response effect. Four unrelated serious AEs were reported (methotrexate: 2, placebo: 2). LIMITATION: Not permitting oral methotrexate to be changed to subcutaneous delivery for intolerance. CONCLUSION: Oral methotrexate added to usual medications demonstrated statistically significant reduction in KOA pain, stiffness, and function at 6 months. PRIMARY FUNDING SOURCE: Versus Arthritis.

BUB1 regulates non-homologous end joining pathway to mediate radioresistance in triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer subtype often treated with radiotherapy (RT). Due to its intrinsic heterogeneity and lack of effective targets, it is crucial to identify novel molecular targets that would increase RT efficacy. Here we demonstrate the role of BUB1 (cell cycle Ser/Thr kinase) in TNBC radioresistance and offer a novel strategy to improve TNBC treatment. METHODS: Gene expression analysis was performed to look at genes upregulated in TNBC patient samples compared to other subtypes. Cell proliferation and clonogenic survivals assays determined the IC50 of BUB1 inhibitor (BAY1816032) and radiation enhancement ratio (rER) with pharmacologic and genomic BUB1 inhibition. Mammary fat pad xenografts experiments were performed in CB17/SCID. The mechanism through which BUB1 inhibitor sensitizes TNBC cells to radiotherapy was delineated by γ-H2AX foci assays, BLRR, Immunoblotting, qPCR, CHX chase, and cell fractionation assays. RESULTS: BUB1 is overexpressed in BC and its expression is considerably elevated in TNBC with poor survival outcomes. Pharmacological or genomic ablation of BUB1 sensitized multiple TNBC cell lines to cell killing by radiation, although breast epithelial cells showed no radiosensitization with BUB1 inhibition. Kinase function of BUB1 is mainly accountable for this radiosensitization phenotype. BUB1 ablation also led to radiosensitization in TNBC tumor xenografts with significantly increased tumor growth delay and overall survival. Mechanistically, BUB1 ablation inhibited the repair of radiation-induced DNA double strand breaks (DSBs). BUB1 ablation stabilized phospho-DNAPKcs (S2056) following RT such that half-lives could not be estimated. In contrast, RT alone caused BUB1 stabilization, but pre-treatment with BUB1 inhibitor prevented stabilization (t1/2, ~8 h). Nuclear and chromatin-enriched fractionations illustrated an increase in recruitment of phospho- and total-DNAPK, and KAP1 to chromatin indicating that BUB1 is indispensable in the activation and recruitment of non-homologous end joining (NHEJ) proteins to DSBs. Additionally, BUB1 staining of TNBC tissue microarrays demonstrated significant correlation of BUB1 protein expression with tumor grade. CONCLUSIONS: BUB1 ablation sensitizes TNBC cell lines and xenografts to RT and BUB1 mediated radiosensitization may occur through NHEJ. Together, these results highlight BUB1 as a novel molecular target for radiosensitization in women with TNBC.

Peak alpha frequency in schizophrenia, bipolar disorder, and healthy volunteers: Associations with visual information processing and cognition.

BACKGROUND: Schizophrenia (SCZ) and bipolar disorder (BD) are associated with information processing abnormalities, including visual perceptual and cognitive impairments, that impact daily functioning. Recent work in healthy samples suggests that peak alpha frequency (PAF) is an electrophysiological index of visual information processing speed that is also correlated with cognitive ability. There is evidence that PAF is slowed in SCZ, but it remains unclear whether PAF is reduced in BD, or if slower PAF is associated with impaired visual perception and cognition in these clinical disorders. METHODS: The current study recorded resting-state brain activity (both eyes open and closed) with electroencephalography (EEG) in 90 SCZ participants, 62 BD participants, and 69 healthy controls. Most participants also performed a visual perception task (backward masking) and cognitive testing (MATRICS Consensus Cognitive Battery). RESULTS: We replicated previous findings of reduced PAF in SCZ compared with healthy controls. In contrast, PAF in BD did not significantly differ from healthy controls. Further, PAF was significantly correlated with performance on the perceptual and cognitive measures in SCZ, but not BD. PAF was also correlated with visual perception in the healthy control group, and showed a trend-level correlation with cognition. CONCLUSIONS: Together, these results suggest that PAF deficits characterize SCZ, but not BD, and that individual differences in PAF relate to abnormalities in visual information processing and cognition in SCZ.

Use of Theoretical Women and Model-Based Compartmental Analysis to Evaluate the Impact of Vitamin A Intake with or without a Daily Vitamin A Supplement on Vitamin A Total Body Stores and Balance During Lactation.

BACKGROUND: Inadequate vitamin A (VA) intake is common among lactating women in many communities worldwide, but high-dose VA supplementation for postpartum women is not recommended by the World Health Organization as an effective intervention. OBJECTIVES: To simulate the impact of VA intake via diet and daily VA supplements on VA total body stores (TBS) and balance in theoretical lactating women with low/moderate TBS. METHODS: We studied 6 theoretical subjects with assigned values for TBS from 219-624 µmol. Using Simulation, Analysis, and Modeling software and a previously published compartmental model for whole-body VA metabolism, we simulated TBS over 6 mo of established lactation for each subject under 4 conditions: 1) prelactation VA intake was increased to maintain VA balance (LSS); 2) prelactation VA intake was maintained (NLSS); 3) VA intake was the same as 2) but a daily VA supplement (2.8 µmol/d) was added (NLSS+S); and 4) VA intake was as 1) and the daily VA supplement was included (LSS+S). RESULTS: To compensate for the loss of VA via milk while VA balance was maintained (LSS) over 6 mo of lactation, VA intake had to increase by 0.8-1.87 µmol/d (n = 6) compared with NLSS. Over 6 mo of NLSS treatment, VA balance was negative (geometric mean, -0.77 µmol/d) compared with LSS, whereas balance was positive under NLSS+S and LSS+S conditions (0.75 and 1.5 µmol/d, respectively). For LSS, the proportion of total VA disposal was 37% via breastmilk, 32% from VA stores, and 32% from nonstorage tissues. CONCLUSIONS: Adding a daily VA supplement (2.8 µmol/d) to the diet of lactating women with suboptimal VA intake may effectively counterbalance the negative VA balance resulting from the output of VA via breastmilk and thus benefit both mother and infant by maintaining or increasing VA stores and breastmilk VA concentration.

Multi-omic Analysis of Human B-cell Activation Reveals a Key Lysosomal BCAT1 Role in mTOR Hyperactivation by B-cell receptor and TLR9.

B-lymphocytes play major adaptive immune roles, producing antibody and driving T-cell responses. However, how immunometabolism networks support B-cell activation and differentiation in response to distinct receptor stimuli remains incompletely understood. To gain insights, we systematically investigated acute primary human B-cell transcriptional, translational and metabolomic responses to B-cell receptor (BCR), Toll-like receptor 9 (TLR9), CD40-ligand (CD40L), interleukin-4 (IL4) or combinations thereof. T-independent BCR/TLR9 co-stimulation, which drives malignant and autoimmune B-cell states, jointly induced PD-L1 plasma membrane expression, supported by NAD metabolism and oxidative phosphorylation. BCR/TLR9 also highly induced the transaminase BCAT1, which localized to lysosomal membranes to support branched chain amino acid synthesis and mTORC1 hyperactivation. BCAT1 inhibition blunted BCR/TLR9, but not CD40L/IL4-triggered B-cell proliferation, IL10 expression and BCR/TLR pathway-driven lymphoma xenograft outgrowth. These results provide a valuable resource, reveal receptor-mediated immunometabolism remodeling to support key B-cell phenotypes including PD-L1 checkpoint signaling, and identify BCAT1 as a novel B-cell therapeutic target.

Evaluation of a unique and innovative diabetes care model in primary care in Ontario, Canada: protocol for a multiple-methods study with a convergent parallel design.

INTRODUCTION: The growth and complexity of diabetes are exceeding the capacity of family physicians, resulting in the demand for community-based, interprofessional, primary care-led transition clinics. The Primary Care Diabetes Support Programme (PCDSP) in London, Ontario, is an innovative approach to diabetes care for high-risk populations, such as medically or socially complex and unattached patients. In this study, we will employ a quadruple-aim approach to evaluate the health system impacts of the PCDSP. METHODS AND ANALYSIS: We will use multiple methods through a convergent parallel design in this project across five unique studies: a case study, a patient study, a provider study, a complications study and a cost-effectiveness study. The project will be conducted in a dedicated stand-alone clinic specialising in chronic disease management, specifically focusing on diabetes care. Participants will include clinic staff, administrators, family physicians, specialists and patients with type 1 or type 2 diabetes who received care at the clinic between 2011 and 2023. The project design will define the intervention, support replication at other sites or for other chronic diseases and address each of the quadruple aims and equity. Following the execution of the five individual studies, we will build a business case by integrating the results. Data will be analysed using both qualitative (content analysis and thematic analysis) and quantitative techniques (descriptive statistics and multiple logistic regression). ETHICS AND DISSEMINATION: We received approval from the research ethics boards at Western University (reference ID: 2023-1 21 766; 2023-1 22 326) and Lawson Health Research Institute (reference ID: R-23-202). A privacy review was completed by St. Joseph's Healthcare Corporation. The findings will be shared among PCDSP staff and patients, stakeholders, academic researchers and the public through stakeholder sessions, conferences, peer-reviewed publications, infographics, posters, media interviews, social media and online discussions. For the patient and provider study, all participants will be asked to provide consent and are free to withdraw from the study, without penalty, until the data are combined. Participants will not be identified in any report or presentation except in the case study, for which, given the number of PCDSP providers, we will seek explicit consent to identify them.

Discovery of Clinical Candidate PF-06648671: A Potent γ-Secretase Modulator for the Treatment of Alzheimer's Disease.

Herein, we describe the design and synthesis of γ-secretase modulator (GSM) clinical candidate PF-06648671 (22) for the treatment of Alzheimer's disease. A key component of the design involved a 2,5-cis-tetrahydrofuran (THF) linker to impart conformational rigidity and lock the compound into a putative bioactive conformation. This effort was guided using a pharmacophore model since crystallographic information was not available for the membrane-bound γ-secretase protein complex at the time of this work. PF-06648671 achieved excellent alignment of whole cell in vitro potency (Aß42 IC50 = 9.8 nM) and absorption, distribution, metabolism, and excretion (ADME) parameters. This resulted in favorable in vivo pharmacokinetic (PK) profile in preclinical species, and PF-06648671 achieved a human PK profile suitable for once-a-day dosing. Furthermore, PF-06648671 was found to have favorable brain availability in rodent, which translated into excellent central exposure in human and robust reduction of amyloid ß (Aß) 42 in cerebrospinal fluid (CSF).

Advancing the Measurement of Social Functioning in Schizophrenia: Applications of Egocentric Social Network Analysis.

People with schizophrenia face challenges with forming and maintaining social relationships, often resulting in poor social functioning. Commonly used measures of social functioning provide broad information relating to social relationships, but they do not adequately capture information regarding network structure and characteristics of network members. One method that can assess these more detailed aspects of social networks and provide a more comprehensive understanding of social functioning deficits is egocentric social network analysis (SNA). SNA is a scientific discipline that uses principles of network science and graph theory to analyze social relations quantitatively. Even though some types of SNA have been applied in prior schizophrenia studies, its application as a framework to measure social functioning has been extremely limited. Therefore, this article aims to formally introduce SNA and select quantitative SNA metrics, including measures of network composition, structure, homophily, and centrality, to schizophrenia researchers as novel ways of measuring components of social functioning. To demonstrate the application of SNA, we provide illustrative examples of the SNA metrics and graphical diagrams of social networks for two individuals with schizophrenia.

PIKfyve, expressed by CD11c-positive cells, controls tumor immunity.

Cancer treatment continues to shift from utilizing traditional therapies to targeted ones, such as protein kinase inhibitors and immunotherapy. Mobilizing dendritic cells (DC) and other myeloid cells with antigen presenting and cancer cell killing capacities is an attractive but not fully exploited approach. Here, we show that PIKFYVE is a shared gene target of clinically relevant protein kinase inhibitors and high expression of this gene in DCs is associated with poor patient response to immune checkpoint blockade (ICB) therapy. Genetic and pharmacological studies demonstrate that PIKfyve ablation enhances the function of CD11c+ cells (predominantly dendritic cells) via selectively altering the non-canonical NF-κB pathway. Both loss of Pikfyve in CD11c+ cells and treatment with apilimod, a potent and specific PIKfyve inhibitor, restrained tumor growth, enhanced DC-dependent T cell immunity, and potentiated ICB efficacy in tumor-bearing mouse models. Furthermore, the combination of a vaccine adjuvant and apilimod reduced tumor progression in vivo. Thus, PIKfyve negatively regulates the function of CD11c+ cells, and PIKfyve inhibition has promise for cancer immunotherapy and vaccine treatment strategies.

Impact of lung cancer screening on stage migration and mortality among the national Veterans Health Administration population with lung cancer.

BACKGROUND: Despite randomized trials demonstrating a mortality benefit to low-dose computed tomography screening to detect lung cancer, uptake of lung cancer screening (LCS) has been slow, and the benefits of screening remain unclear in clinical practice. METHODS: This study aimed to assess the impact of screening among patients in the Veterans Health Administration (VA) health care system diagnosed with lung cancer between 2011 and 2018. Lung cancer stage at diagnosis, lung cancer-specific survival, and overall survival between patients with cancer who did and did not receive screening before diagnosis were evaluated. We used Cox regression modeling and inverse propensity weighting analyses with lead time bias adjustment to correlate LCS exposure with patient outcomes. RESULTS: Of 57,919 individuals diagnosed with lung cancer in the VA system between 2011 and 2018, 2167 (3.9%) underwent screening before diagnosis. Patients with screening had higher rates of stage I diagnoses (52% vs. 27%; p ≤ .0001) compared to those who had no screening. Screened patients had improved 5-year overall survival rates (50.2% vs. 27.9%) and 5-year lung cancer-specific survival (59.0% vs. 29.7%) compared to unscreened patients. Among screening-eligible patients who underwent National Comprehensive Cancer Network guideline-concordant treatment, screening resulted in substantial reductions in all-cause mortality (adjusted hazard ratio [aHR], 0.79; 95% confidence interval [CI], 0.67-0.92; p = .003) and lung-specific mortality (aHR, 0.61; 95% CI, 0.50-0.74; p < .001). CONCLUSIONS: While LCS uptake remains limited, screening was associated with earlier stage diagnoses and improved survival. This large national study corroborates the value of LCS in clinical practice; efforts to widely adopt this vital intervention are needed.

Defeatist performance beliefs in individuals with recent-onset schizophrenia: Relationships with cognition and negative symptoms.

BACKGROUND: The cognitive model of negative symptoms of schizophrenia suggests that defeatist performance beliefs (DPB), or overgeneralized negative beliefs about one's performance, are an intermediary variable along the pathway from impaired neurocognitive performance to negative symptoms and functioning in daily life. Although reliable associations between these variables have been established in chronic schizophrenia, less is known about the nature of these relationships in recent-onset schizophrenia (ROSz). This current study tested the associations between DPB and variables in the cognitive model (neurocognitive performance, negative symptoms, functioning) as well as mediation by DPB of the association between neurocognitive performance and negative symptoms in ROSz. METHODS: A total of 52 participants (32 adults with ROSz and 20 non-psychiatric healthy comparators; HC) completed in-lab measures of neurocognitive performance, self-reported defeatist performance beliefs, and clinician administered measures of negative symptoms and functional outcome. Bivariate relationships among these variables were tested with Pearson correlations. Bootstrapped regression analyses were conducted to test the strength of the indirect effect of neurocognitive performance on negative symptoms through DPB. RESULTS: Defeatist performance beliefs were significantly elevated in ROSz, and were associated with neurocognitive performance, negative symptoms, and functional outcome as predicted by the cognitive model. There was a significant indirect effect of neurocognition on experiential negative symptoms through DPB, indicating DPB are a partial mediator of the relationship between neurocognitive performance and negative symptoms. CONCLUSION: These findings are consistent with the cognitive model of negative symptoms and extend previous findings in both ROSz and established schizophrenia. Specifically, these data demonstrate that DPB are elevated among ROSz and the associations with neurocognition and clinical outcomes (e.g., negative symptoms and functioning) are of similar magnitude to those reported in chronic schizophrenia. DPB may therefore be a viable treatment target in the early course of illness.

Stress-related gene regulation: Do isolated and connected individuals differ?

BACKGROUND: Social isolation and loneliness (known as social disconnection, collectively) lead to serious downstream health effects, including shortening of lifespan and higher risk for cardiac disease. We must better understand how isolation and loneliness lead to these negative health outcomes. Previous literature has demonstrated that social motivation and social ability are contributors to the likelihood of social isolation and loneliness. We examined the effect of the above social factors on immune gene expression in socially-connected and -isolated individuals. METHODS: Recruitment occurred via two online advertisements, one for socially isolated individuals and another for general research participants. Participants (n = 102) were separated into groups (isolated versus connected) based on which ad they responded to, and provided data on isolation, loneliness, social motivation, and social ability. The Conserved Transcriptional Response to Adversity (CTRA) stress gene regulation program was assessed with genome-wide transcriptional profiling. RESULTS: CTRA gene expression patterns were reversed between connected and isolated groups across several variables. Social isolation was associated with higher CTRA levels in the connected group, but lower levels in the isolated group. Social approach was associated with lower CTRA levels in the connected group, but higher in the isolated group, and the converse was true for social avoidance. CTRA levels were minimally affected by social ability measures. CONCLUSION: Prior work on social isolation and loneliness has focused on loneliness and has identified many negative downstream health effects. In this study we demonstrate that objective social isolation may not be associated with the same negative downstream health effects, and in fact, social interaction may be more stressful than social isolation for some socially-isolated individuals.

Care-seeking experiences of unattached patients in the Canadian health care system: Qualitative study.

OBJECTIVE: To understand how lack of attachment to a regular primary care provider influences patients' outlooks on primary care, ability to address their health care needs, and confidence in the health care system. DESIGN: Qualitative descriptive study using semistructured interviews. SETTING: Canadian provinces of Nova Scotia, Ontario, and Quebec. PARTICIPANTS: Patients aged 18 years or older who were unattached or had become attached within 1 year of being interviewed and who resided in the province in which they were interviewed. METHODS: Forty-one semistructured interviews were conducted, during which participants were asked to describe how they had become unattached, their searches to find new primary care providers, their perceptions of and experiences with the centralized waiting list in their province, their experiences seeking care while unattached, and the impact of being unattached on their health and on their perceptions of the health care system. Interviews were transcribed and analyzed using a thematic approach. MAIN FINDINGS: Two main themes were identified in interviews with unattached or recently attached patients: unmet needs of unattached patients and the impact of being unattached. Patients' perceived benefits of attachment included access to care, longitudinal relationships with health care providers, health history familiarity, and follow-up monitoring and care coordination. Being unattached was associated with negative effects on mental health, poor health outcomes, decreased confidence in the health care system, and greater pre-existing health inequities. CONCLUSION: Having a regular primary care provider is essential to having access to high-quality care and other health care services. Attachment also promotes health equity and confidence in the public health care system and has broader system-level, social, and policy implications.