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This pilot randomized control trial (RCT) tested “Do More, Feel Better” (DMFB), a lay-delivered Behavioral Activation intervention for depressed senior center clients. The study examined: 1. the feasibility of training older lay volunteers to fidelity; and 2. the acceptability, safety, and impact of the intervention. Twenty-one lay volunteers at four senior centers were trained in DMFB. Fifty-six depressed clients were randomized to receive 9 sessions of DMFB or Behavioral Activation delivered by social workers (MSW BA). Research assessments of overall client activity level (BADS) and depression severity (HAM-D) were conducted at baseline and weeks 3, 6, and 9. Eighty-one percent of lay volunteers who underwent training were formally certified in DMFB. Depressed clients receiving each intervention reported high levels of satisfaction and showed large and clinically significant changes in 9-week activity level (d ≥ 1.35) and depression severity (d ≥ 3.34). Differences between treatment groups were very small for both activity level (dMSW = 0.16; 95% CI, -0.70 to 1.02) and depression (dMSW = 0.14; 95% CI, -0.63 to 0.91). Increases in activity level were associated with decreases in depression (β = -0.42; 95% CI, -0.55 to -0.30). Both interventions appeared to work as intended by increasing activity level and reducing depression severity. “Do More, Feel Better” shows the potential of evidence-based behavioral interventions delivered by supervised lay volunteers, and can help address the insufficient workforce available to meet the mental health needs of community-dwelling older adults.

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This supplemental file contains data that supports the claims and results described in the main manuscript. Figures include full mass spectra data acquired for the representative thyroid samples, examples of fragmentation patterns obtained for all the main molecular classes identified, mass spectra results obtained for confirmatory experiments using lipid standards, examples of 2D DESI-MS ion images and mass spectra for several additional samples, optical images of immunohistochemistry results, mass spectra results for isolated mitochondria experiments, and a table with detailed identification results for all molecules described in the main manuscript.

Oncocytic tumors are characterized by an excessive eosinophilic, granular cytoplasm due to aberrant accumulation of mitochondria. Mutations in mitochondrial DNA occur in oncocytic thyroid tumors, but there is no information about their lipid composition, which might reveal candidate theranostic molecules. Here, we used desorption electrospray ionization mass spectrometry (DESI-MS) to image and chemically characterize the lipid composition of oncocytic thyroid tumors, as compared with nononcocytic thyroid tumors and normal thyroid samples. We identified a novel molecular signature of oncocytic tumors characterized by an abnormally high abundance and chemical diversity of cardiolipins (CL), including many oxidized species. DESI-MS imaging and IHC experiments confirmed that the spatial distribution of CLs overlapped with regions of accumulation of mitochondria-rich oncocytic cells. Fluorescent imaging and mitochondrial isolation showed that both mitochondrial accumulation and alteration in CL composition of mitochondria occurred in oncocytic tumors cells, thus contributing the aberrant molecular signatures detected. A total of 219 molecular ions, including CLs, other glycerophospholipids, fatty acids, and metabolites, were found at increased or decreased abundance in oncocytic, nononcocytic, or normal thyroid tissues. Our findings suggest new candidate targets for clinical and therapeutic use against oncocytic tumors. Cancer Res; 76(22); 6588–97. ©2016 AACR.

This supplemental file contains detailed descriptions of the methods employed in the research reported in the main manuscript, including the methods used for molecular imaging experiments using DESI-MS, immunohistochemistry and immunofluorescence assays, mitochondria isolation and analysis, and histopathologic evaluation of tissue samples.

Current preclinical models for cervical cancer lack important clinical and pathologic features. To improve upon these models, we aimed to develop a novel, spontaneous HPV16-expressing carcinoma model that captures major aspects of HPV-associated cancer in the female genital tract. This novel preclinical model features (i) expression of HPV oncogenes E6 and E7 in the tumors in female reproductive tract of mice, (ii) spontaneous progression through high-grade squamous intraepithelial lesion (HSIL) to carcinoma, and (iii) flexibility to model cancers from different high-risk HPV genotypes. This was accomplished by injecting plasmids expressing HPV16 E6/E7-luciferase, AKT, c-myc, and Sleeping Beauty transposase into the cervicovaginal tract of C57BL/6 mice followed by electroporation. Cell lines derived from these tumors expressed HPV16 E6/E7 oncogenes, formed tumors in immunocompetent mice, and displayed carcinoma morphology. In all, this novel HPV-associated cervicogenital carcinoma model and HPV16E6/E7–expressing tumor cell line improves upon current HPV16-E6/E7–expressing tumor models. These tumor models may serve as important preclinical models for the development of therapeutic HPV vaccines or novel therapeutic interventions against HPV E6/E7–expressing tumors.Significance:This study describes the development of a clinically relevant mouse model of cervicovaginal carcinoma that progresses from high-grade lesions and recapitulates key features of human HPV+ cervical cancer.

Clinical Practice Points • Carfilzomib (CFZ) has rarely been associated with atypical hemolytic uremic syndrome (aHUS). • Patients with heterozygous complement factor H related protein 3 (CFHR)/CFHR1 deletions may be predisposed to CFZ-induced aHUS. • The benefit of eculizumab in the treatment of CFZ-induced aHUS that fails to improve with drug withdrawal and supportive care remains uncertain.

The COVID-19 pandemic led to growing concerns about pilots' proficiency due to the significant decrease in flight operations. The objective of this research is to provide a proactive approach to mitigate potential risks in flight operations associated with the impact of the COVID-19 pandemic using flight data monitoring (FDM). The results demonstrated significant associations between the pandemic impacts and FDM exceedance categories, flight phases and fleets. Manual flying skill decay, lack of practice effects on use of standard operating procedures and knowledge of flight deck automation should be considered by airlines when preparing for the return to normal operations. An FDM Programme allows prediction of the probability and severity of occurrences for developing an effective SMS within an airline. To mitigate the impacts of the pandemic, tailored training sessions must be implemented, and airlines should strive to avoid additional optional procedures where practicable.The COVID-19 pandemic has raised concerns regarding pilot proficiency due to lack of practice effects. Flight Data Monitoring Programme shows significant associations between the pandemic impacts and occurrence categories, fleets, and flight phases. FDM can be applied to mitigate the probability and severity of occurrences for airlines developing effective safety management systems.

Background In the United States, human papillomavirus (HPV) vaccination has been recommended since 2011 for boys aged 11–12 years, with catch-up vaccination recommended through age 26 years for previously unvaccinated men who have sex with men (MSM). Methods During 2016–2018, a cross-sectional study enrolled MSM and transgender women aged 18–26 years in Seattle, Washington. Participants submitted self-collected penile swab specimens for HPV genotyping. HPV vaccination history was self-reported. We compared HPV prevalence among vaccinated participants with that in participants with no or unknown vaccination history, using log-binomial regression to estimate adjusted prevalence ratios and confidence intervals. Results Among 687 participants, 348 (50.7%) self-reported ever receiving ≥1 HPV vaccine dose; the median age at first HPV vaccination was 21 years, and the median age at first sex, 17 years. Overall, the prevalence of penile quadrivalent HPV vaccine (4vHPV)–type HPV was similar in vaccinated participants (12.1%) and participants with no or unknown vaccination (15.6%) (adjusted prevalence ratio, 0.69 [95% confidence interval, .47–1.01]). However, the prevalence was significantly lower in participants vaccinated at age ≤18 years than in those with no of unknown vaccination (0.15 [.04–.62]), corresponding to a vaccine effectiveness of 85% against 4vHPV-type HPV. Conclusions Results suggest that HPV vaccination is effective in preventing penile HPV infections in young MSM when administered at age ≤18 years.

Purpose Exercise therapy (ET) is shown to improve toxicity and surrogates of survival for patients receiving chemotherapy. Current National Comprehensive Cancer Network (NCCN) guidelines lack recommendations for concurrent radiation therapy (RT) and ET. The main objective was to determine the impact of concurrent ET + RT with respect to (1) acceptability, feasibility, safety; and (2) to demonstrate how incorporating ET in cancer treatment can enhance patient-reported outcomes (PROs) and physical function—defined as strength or exercise capacity. Methods and Materials A PICOS/PRISMA selection protocol was used to search PubMed, Cumulative Index of Nursing and Allied Health Literature (CINAHL), and Cochrane Review for prospective randomized controlled trials evaluating concurrent ET + RT, including >10 patients and with 1 or more study arms. Acceptability, feasibility, and safety rates were calculated. PROs were assessed with study-specific metrics. Physical function was defined as improvements in strength or range of motion. Statistically significant improvement was defined by P Results Twenty-six of 693 screened studies including 1563 patients (831 receiving exercise, 732 controls) with localized breast cancer (67.1% of patients), prostate cancer (27.4%), head and neck cancers (2.8%), and spinal metastases (2.8%) were assessed. Objective 1: Among 3385 patients approached for ET, 1864 (55.1%) accepted the treatment; of those, 1563 patients (83.9%) completed the trials. Objective 2: Statistical improvements were noted in these PROs: quality of life (14 of 15 studies), fatigue (12 of 16 studies), mood/depression (9 of 13), and anxiety (6 of 7). Physical function improved statically in 16 of 16 studies. Conclusions Combination ET + RT is safe and well-tolerated with improvements in PROs and physical function. Additional studies are needed in patients with metastatic cancers to assess survival and to compare effectiveness of different exercise regimens.

Mailing HPV self-sampling kits to overdue individuals increases cervical cancer screening adherence; offering self-sampling to previously adherent individuals has not been evaluated in the U.S. Given heterogeneity of the U.S. health system and population, data are needed to optimize how HPV self-sampling is offered to individuals who are overdue, due after successful past screening, or have an unknown screening history.STEP is a pragmatic randomized controlled trial set within a U.S. integrated healthcare delivery system, designed to compare different outreach approaches for offering HPV self-sampling in populations defined by prior screening behavior (previously-adherent, overdue, or unknown screening history). Over 14 months, eligible individuals were identified through electronic medical record (EMR) data and randomized to Usual Care (UC), Education (UC + educational materials about cervical cancer screening), Direct-Mail (UC + Education + a mailed self-sampling kit) or Opt-In (UC + Education + option to request a kit), depending on screening history. The primary objective is to compare screening completion by outreach approach and screening history. Secondary objectives include evaluating incremental cost-effectiveness of outreach approaches, and identifying patient preference for, and satisfaction with, HPV self-screening, and barriers to abnormal results follow-up (measured through interviews and focus groups).The trial was designed to generate data that U.S. health systems can use to inform primary HPV screening implementation strategies that incorporate HPV self-sampling options to improve screening access, adherence, and patient satisfaction. The objective of this report is to describe the rationale and design of this pragmatic trial.

Background Persistent infection with high-risk human papillomavirus (HPV) is associated with development of invasive cervical cancer. Methods Longitudinal data was collected from 174 Senegalese women. We employed marginal Cox proportional hazards models to examine the effect of human immunodeficiency virus (HIV) status (HIV positive vs HIV negative) and HIV type (HIV-1 vs HIV-2 vs dual HIV-1/HIV-2) on clearance of type-specific HPV infection. Analyses were stratified by incident versus prevalent HPV infection. Results Incident HPV infections in HIV-positive women were less likely to clear than those in HIV-negative women (adjusted hazard ratio [HR] = 0.60; 95% confidence interval [CI], .38–.94). Among HIV-positive women, HIV-2–infected women and HIV-1/2 dually infected women were more likely to clear HPV incident infections than HIV-1–infected women (HR = 1.66; 95% CI, .95–2.92 and HR = 2.17; 95% CI, 1.12–4.22, respectively). Incident HPV infections in HIV-positive women with CD4 cell count ≤500 cells/μL were less likely to clear than those in HIV-positive women with CD4 cell count >500 cells/μL (HR = 0.65; 95% CI, .42–1.01). No significant associations were observed for prevalent HPV infections. Conclusions HIV infection reduced the likelihood of clearance of incident HPV infection. Furthermore, among HIV-positive women, low CD4 cell count and dual HIV infection were each associated with reduced likelihood of clearance.

Increasing evidence points to the role of endogenous retroviruses (ERVs) in driving cancer cell proliferation. The purpose of this study was to explore the possibility of repurposing antiretroviral agents to inhibit ERVs as a new approach in cancer treatment. We found that an integrase strand-transfer inhibitor, dolutegravir (DTG), effectively inhibited the proliferation of multiple cancer cell lines and its antiproliferative potency was positively correlated with the expression levels of the human endogenous retrovirus type K (HERV-K). DTG inhibited the expression of HERV-K in multiple human cancer cell lines and the mouse mammary tumor virus (MMTV) in the murine 4T1 mammary cancer cell line. We chose the fast-growing BT-20 cell line as a model to study the in vitro antiproliferative mechanisms of DTG. BT-20 cells overexpressing both HERV-K env and pol genes became more resistant to DTG than cells transduced with vector alone. Knockdown of HERV-K also increased DTG resistance of BT-20 cells. The antiproliferative effect of DTG correlated with enhanced expression of E-cadherin and reduction in cell motility and invasiveness. Surprisingly, DTG stimulated expression of the env gene of MMTV in vivo and promoted metastasis of 4T1 tumor cells to the lungs. Taken together, our data support a role of ERVs in tumor development and encourage further search for antiretroviral agents to treat malignancies in which endogenous retroviruses are active.

The clinical success of cancer immunotherapy, including engineered T cell therapies, has revolutionized treatment paradigms and patient outcomes. While hematological tumors have benefited most from cell therapy approaches, the treatment of solid tumors remains a challenge in part due to the limited availability of abundant and tumor-specific cell-surface antigens. Peptides derived from intracellular tumor-specific proteins, such as cancer-testis antigens (CTAs), that are presented via HLA (pHLA) enable a therapeutic opportunity to target tumors while sparing normal tissue. Surface-accessible pHLA complexes may be targeted with engineered T cell receptors or TCR mimetic antibodies reformatted to chimeric antigen receptors (CARs). Using MAGE-A4 as a model CTA, we compared engineered human TCR- and CAR-T cells head-to-head to understand how to best deploy these modalities. To this end, we generated fully-human, HLA-A2/MAGE-A4(230-239)-specific TCR and CARs harboring CD28/CD3z or 41BB/CD3z signaling domains. TCR and CAR-T cells demonstrated similar robust on-target reactivity, cytokine release, and target cell lysis in vitro. In vivo, each of these modalities showed potent, dose-dependent anti-tumor efficacy against human xenograft tumors expressing low, endogenous levels (~500 cell-surface copies) of the MAGE-A4 peptide. However, differences emerged when we examined the in vivo kinetics and durability of tumor suppression. MAGE-A4 CD28/z CAR-T demonstrated the most rapid and potent tumor clearance, while the 41BB/z CAR-T showed delayed but ultimately complete efficacy. TCR-T cells induced tumor regressions during the first 2 weeks of treatment, but this response was transient and followed by tumor relapse. These differential responses correlated with early, modest accumulation of CD28/z CAR-T in line with fast tumor clearance. 41BB/z CAR-T showed a remarkable ~800-fold expansion in the tumor versus limited in vivo TCR-T proliferation. Mechanistically, the MAGE-A4 TCR induced strong CD3 proximal signaling associated with a greater induction of T cell dysfunction markers and limited cytotoxic potential in vitro. However, stimulating 41BB signaling pathways in the MAGE-A4 TCR T cells augmented long-term cytotoxicity. These data demonstrate that tumor-specific pHLA complexes can be potently targeted by both TCR and CAR-T cells, and that co-stimulatory signaling is necessary to mediate durable anti-tumor activity. Citation Format: Corinne E. Decker, Jacqueline Idun, Katja Mohrs, Thomas Meagher, Kevin Bray, Iryna Petriv, Jonathon Golas, Timothy Helms, Dharani Ajithdoss, Gavin Thurston, John Lin, Jessica R. Kirshner, David J. DiLillo. TCR-T and CAR-T cells targeting HLA-A2/MAGEA4 demonstrate differential tumor control, reflecting co-stimulatory signaling requirements [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1780.

High endothelial venules (HEV) are specialized blood vessels that mediate lymphocyte trafficking to lymph nodes. Tertiary lymphoid structures (TLS) are ectopic lymphoid formations that develop in inflamed, infected or tumoral tissues. TLS contain HEV and B cell follicles surrounded by a T-cell zone and are characterized by abundant chemokine expression. The presence of TLS and HEV in solid tumors is positively correlated with patient survival in many cancer types, and may even be predictive of better response to immune-checkpoint blockade. However, the molecular mechanisms underlying the intratumoral HEV and TLS formation remain unclear. Using murine syngeneic tumor models, we found that systemic activation of lymphotoxin beta receptor (LTBR) with an agonistic antibody induced tumor-specific HEV formation, increased dendritic cell (DC) and T cell infiltration, and enhanced T cell activation in the tumor. In vitro assays revealed that LTBR agonism directly upregulated activation and maturation markers in bone marrow-derived DCs and promoted DC-mediated CD4 and CD8 T cell activation. Single agent LTBR agonist treatment attenuated Colon26 tumor growth in a CD8 T cell-dependent manner. In combination treatment studies, LTBR agonism further augmented anti-tumor efficacy of anti-PD1 and of CAR-T therapy. Notably, LTBR agonist mAb treatment upregulated the expression of TLS-related chemokines and induced TLS-like structures in approximately 20% of treated tumors. To enhance TLS induction, we generated syngeneic tumor models engineered to express several cytokines/chemokines and performed an in vivo screen for tumor-associated TLS formation. We identified some factors that in combination with LTBR agonism induced B cell enrichment and immature TLS formation, while others promoted robust TLS induction and anti-tumor effect. TLS formation induced by combined LTBR agonism and cytokine expression is associated with augmented anti-tumor responses to anti-CTLA-4 treatment. By studying anti-tumor mechanisms of LTBR agonism-mediated HEV and TLS formation, this work informs the future therapeutic strategies to boost T cell infiltration and activation in solid tumors. Citation Format: Disi An, Guoying Chen, Wei Wang, Katja Mohrs, David DiLillo, Christopher Daly, Gavin Thurston, John Lin, Namita Gupta, Mickey Atwal, Frank Kuhnert. Boosting anti-tumor immunity by promoting high endothelial venule and tertiary lymphoid structure formation in solid tumors via LTBR agonism. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4134.

This study investigates how the configuration of rivals and collaborators within a firm’s alliance portfolio affects its speed of absorbing external knowledge (i.e., absorption speed). While prior research on learning alliances has predominantly focused on interfirm overall knowledge flows, we contend that absorption speed plays a critical role in technology-intensive industries where time-based competition is paramount. Additionally, most previous studies do not clearly distinguish a firm’s rivals from its collaborators within the alliance portfolio. Building on interorganizational learning theory, we propose that a simultaneous and balanced presence of both rivals and collaborators within a firm’s alliance portfolio, which we term relational ambidexterity, increases the firm’s speed of absorbing external knowledge. We further contend that while a firm’s internal knowledge variety strengthens the positive relationship between relational ambidexterity and absorption speed, the number of common third parties between a firm and its partner weakens this positive relationship. The results of an event history study of 467 firms in the pharmaceutical industry of the United States from 1990 to 2010 provide general support for our hypotheses.

Gene therapy, cell therapy and vaccine research have led to an increased use of qPCR/ddPCR in bioanalytical laboratories. CROs are progressively undertaking the development and validation of qPCR and ddPCR assays. Currently, however, there is limited regulatory guidance for the use of qPCR and a complete lack of any regulatory guidelines for the use of the newer ddPCR to support regulated bioanalysis. Hence, the Global CRO Council in Bioanalysis (GCC) has issued this White Paper to provide; 1) a consensus on the different validation parameters required to support qPCR/ddPCR assays; 2) a harmonized approach to their validation and 3) a consistent development of standard operating procedures (SOPs) for all the bioanalytical laboratories using these techniques.

Cachexia is a metabolic mutiny that directly reduces life expectancy in chronic conditions such as cancer. The underlying mechanisms associated with cachexia involve inflammation, metabolism, and anorexia. Therefore, the need to identify cachexia biomarkers is warranted to better understand catabolism change and assess various therapeutic interventions. Among inflammatory proteins, growth differentiation factor-15 (GDF15), an atypical transforming growth factor-beta (TGF-β) superfamily member, emerges as a stress-related hormone. In inflammatory conditions, cardiovascular diseases, and cancer, GDF15 is a biomarker for disease outcome. GDF15 is also implicated in energy homeostasis, body weight regulation, and plays a distinct role in cachexia. The recent discovery of its receptor, glial cell line-derived neurotrophic factor (GDNF) family receptor α-like (GFRAL), sheds light on its metabolic function. Herein, we critically review the mechanisms involving GDF15 in cancer cachexia and discuss therapeutic interventions to improve outcomes in people living with cancer.

ImportanceHuman papillomavirus (HPV) self-sampling addresses barriers to cervical cancer screening, and mailed self-sampling kits have been reported to increase screening uptake. International research suggests mailed kits are cost-effective in certain settings. However, the cost-effectiveness of mailing HPV self-sampling kits for increasing screening uptake has not been evaluated in the US.ObjectiveTo conduct an economic evaluation of a mailed HPV self-sampling intervention among underscreened women enrolled in an integrated US health care system.Design, Setting, and ParticipantsThis economic evaluation involved a cost-effectiveness analysis of results from a randomized clinical trial of 19 851 women aged 30 to 64 years enrolled in a health plan from Kaiser Permanente Washington (KPWA), a US-based integrated health care system. Women were identified through electronic medical records, and eligible participants were enrolled in a health plan for at least 3 years and 5 months, had a primary care clinician, had not received a Papanicolaou test for at least 3 years and 5 months, and had not received a hysterectomy. Enrollment occurred from February 25, 2014, to August 29, 2016, with follow-up through February 25, 2018. The current economic evaluation was conducted between August 2, 2021, and July 30, 2022. Intervention delivery costs were calculated from both the KPWA and Medicare perspectives and were based on either wellness visit or Papanicolaou test–only visit costs.InterventionParticipants in the control group received usual care, which comprised patient reminders and ad hoc outreach for screening. Participants in the intervention group received usual care plus a mailed HPV self-sampling kit.Main Outcome and MeasuresThe primary economic outcome was the incremental cost-effectiveness ratio (ICER) for increased screening uptake, defined as the incremental difference in cost (intervention group minus control group) divided by the difference in the number of participants completing screening (intervention group minus control group) within 6 months of randomization.ResultsAmong 19 851 women (mean [SD] age, 50.1 [9.5] years; 76.7% White), 9960 were randomized to the intervention group, and 9891 were randomized to the control group. Baseline ICERs ranged from $85.84 (95% CI, $85.68-$85.99) using KPWA wellness visits as the cost basis to $146.29 (95% CI, $146.20-$146.38) using Medicare Papanicolaou test–only visits as the cost source. Subgroups of participants aged 50 to 64 years and participants most recently overdue for screening achieved cost-effectiveness at lower levels of willingness to pay for an additional completed screening than other subgroups.Conclusions and RelevanceIn this economic evaluation, mailing HPV self-sampling kits to women overdue for cervical cancer screening was cost-effective for increased screening uptake relative to usual care. These results support mailing HPV kits as an efficient outreach strategy for increasing screening rates among eligible women in US health care systems.

Background: Over 14,000 cervical cancers are diagnosed annually in the U.S. In 2019, ~30% of individuals with a cervix were under-screened based on current guidelines. Previous studies established feasibility of mailed self-sampling high-risk HPV test kits to improve screening adherence. Qualitative findings from our HOME trial found unmet information needs and anxiety among patients with a positive kit result. We designed the STEP trial to test optimized implementation strategies for educating patients about screening when offering the kit to patients due/overdue for screening, and when reporting results. Purpose: To evaluate acceptability of the implementation strategies, we interviewed individuals after receiving a positive kit result about the result communication processes and their information needs. Methods: The STEP trial added a centralized licensed practical nurse to communicate about and arrange scheduling for all patients with positive kit results, and provided an educational pamphlet to explain the purpose of HPV testing (especially difference to Pap testing) and how latent infections can reactivate. Telephone interviews were conducted from December 2021 to March 2022 with 29 patients (56% of invited) who had a positive kit result. Interview guide asked about reaction to the kit, results communication, patient-provider interactions, and follow-up visit experiences; and included a survey regarding attitudes toward the kit. Five coders analyzed interview transcripts using iterative content analysis; 12 transcripts were double-coded. Codes were organized into node reports to identify overarching themes. Results: Of 29 participants, most (65.5%) were non-Hispanic White and the average age was 47.5 years (SD=11.2). Participants appreciated the convenience of the kit, though a few worried about the accuracy of self-sampling test results, especially compared to screening performed by a provider. While surprised by the positive kit result, all reported feeling reassured after talking with the nurse and understood next steps in the diagnosis and management process, although some reported still wanting to check with their primary care provider about the test findings. Though an educational pamphlet was provided with the home HPV kit, most participants did not recall receiving it or using it to understand their kit results. After reflecting on home kit versus in-clinic screening, most (69%) preferred using the kit on their own to provider-collected screening. All (100%) agreed that the kit instructions were easy to understand, however 90% were sure that they had sampled the right place, and 86% believed that the home test results were correct. Discussion: Unlike the prior HOME trial, there was less negative affect expressed by patients after receiving results. This suggests patients received the information needed to continue with the screening process and supports the value of a centralized nurse. Providing educational materials at multiple timepoints may further improve results communication in the future. Citation Format: Meera Muthukrishnan, Jasmin A. Tiro, Kris Hansen, John Lin, Caitlin Dorsey, Hongyuan Gao, Catherine Troja, Melissa Anderson, Richard Meenan, Beverly B. Green, Diana S.M. Buist, Rachel Winer. Improving communication and management following a positive home HPV self-sampling kit result [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr A108.

Given that high-risk human papillomavirus (HPV) is the necessary cause of virtually all cervical cancer, the clinical meaning of HPV-negative cervical precancer is unknown. We, therefore, conducted a literature search in Ovid MEDLINE, PubMed Central, and Google Scholar to identify English-language studies in which (i) HPV-negative and -positive, histologically confirmed cervical intraepithelial neoplasia grade 2 or more severe diagnoses (CIN2+) were detected and (ii) summarized statistics or deidentified individual data were available to summarize proportions of biomarkers indicating risk of cancer. Nineteen studies including 3,089 (91.0%) HPV-positive and 307 (9.0%) HPV-negative CIN2+ were analyzed. HPV-positive CIN2+ (vs. HPV-negative CIN2+) was more likely to test positive for biomarkers linked to cancer risk: a study diagnosis of CIN3+ (vs. CIN2; 18 studies; 0.56 vs. 0.24; P < 0.001) preceding high-grade squamous intraepithelial lesion cytology (15 studies; 0.54 vs. 0.10; P < 0.001); and high-grade colposcopic impression (13 studies; 0.30 vs. 0.18; P = 0.03). HPV-negative CIN2+ was more likely to test positive for low-risk HPV genotypes than HPV-positive CIN2+ (P < 0.001). HPV-negative CIN2+ appears to have lower cancer risk than HPV-positive CIN2+. Clinical studies of human high-risk HPV testing for screening to prevent cervical cancer may refer samples of HPV test–negative women for disease ascertainment to correct verification bias in the estimates of clinical performance. However, verification bias adjustment of the clinical performance of HPV testing may overcorrect/underestimate its clinical performance to detect truly precancerous abnormalities.

Gene therapy, cell therapy and vaccine research have led to an increased need to perform cellular immunity testing in a regulated environment to ensure the safety and efficacy of these treatments. The most common method for the measurement of cellular immunity has been Enzyme-Linked Immunospot assays. However, there is a lack of regulatory guidance available discussing the recommendations for developing and validating these types of assays. Hence, the Global CRO Council has issued this white paper to provide a consensus on the different validation parameters required to support Enzyme-Linked Immunospot assays and a harmonized and consistent approach to Enzyme-Linked Immunospot validation among contract research organizations.

Antimicrobial and diagnostic stewardship initiatives have become increasingly important in paediatric settings. The value of qualitative approaches to conduct stewardship work in paediatric patients is being increasingly recognized. This article seeks to provide an introduction to basic elements of qualitative study designs and provide an overview of how these methods have successfully been applied to both antimicrobial and diagnostic stewardship work in paediatric patients. A multidisciplinary team of experts in paediatric infectious diseases, paediatric critical care and qualitative methods has written a perspective piece introducing readers to qualitative stewardship work in children, intended as an overview to highlight the importance of such methods and as a starting point for further work. We describe key differences between qualitative and quantitative methods, and the potential benefits of qualitative approaches. We present examples of qualitative research in five discrete topic areas of high relevance for paediatric stewardship work: provider attitudes; provider prescribing behaviours; stewardship in low-resource settings; parents’ perspectives on stewardship; and stewardship work focusing on select high-risk patients. Finally, we explore the opportunities for multidisciplinary academic collaboration, incorporation of innovative scientific disciplines and young investigator growth through the use of qualitative research in paediatric stewardship. Qualitative approaches can bring rich insights and critically needed new information to antimicrobial and diagnostic stewardship efforts in children. Such methods are an important tool in the armamentarium against worsening antimicrobial resistance, and a major opportunity for investigators interested in moving the needle forward for stewardship in paediatric patients.

IntroductionDespite the success of antiretroviral therapy (ART) in transforming HIV disease into a chronic infection, people living with HIV (PLWH) remain at risk for various non-AIDS inflammatory comorbidities. Risk of non-AIDS comorbidities is associated with gut dysbiosis, epithelial gut damage and subsequent microbial translocation, and increased activation of both circulating CD4+ and CD8+ T-cells. Therefore, in addition to ART, novel gut microbiota-modulating therapies could aid in reducing inflammation and immune activation, gut damage, and microbial translocation. Among various gut-modulation strategies under investigation, the Amazonian fruit Camu Camu (CC) presents itself as a prebiotic candidate based on its anti-inflammatory and antioxidant properties in animal models and tobacco smokers.Method and analysisA total of 22 PLWH on ART for more than 2 years, with a viral load 200 and a CD4+/CD8 +ratio Ethics and disseminationThe Canadian Institutes of Health Research (CIHR)/Canadian HIV Trials Network (CTN) pilot trial protocol CTNPT032 was approved by the Natural and Non-prescription Health Products Directorate of Health Canada and the research ethics board of the McGill university Health Centre committee (number 2020-5903). Results will be made available as free access through publications in peer-reviewed journals and through the CIHR/CTN website.Trial registration numberNCT04058392.

Early establishment of HIV reservoir represents the main impediment to an HIV cure. Mainly composed of infected memory CD4 T-cells and macrophages, HIV reservoirs are found in several organs including lymph nodes, gut, and testes. In men, and as seen in brain and eyes, testes represent a distinctive organ characterized by an immune privilege, allowing the tolerance of spermatozoa which only develop after puberty, long after the establishment of systemic immunity. The immune privilege of testes relies on a strict testis-blood barrier, and a local immunosuppressive environment. Testes has been described as reservoir for several viruses including Ebola, Zika, and HIV. Indeed, HIV reservoirs were detected in tested viremic and virally suppressed donor taking antiretroviral therapy (ART). Herein, we discuss the distinctive environment found in human testes and describe a validated method allowing the characterization and quantification of HIV-infected CD4 T-cells in human testes. Using mechanical and enzymatic treatment, cells can be extracted from human testis samples. Characterization of those cells can be performed by flow cytometry and HIV reservoir quantification performed by nested qPCR after flow cytometry sorting.

There have been significant advances in the technique and application of endovascular repair of thoracic aortic pathology over the past 20 years. The Stanford type A and the complicated type B dissection patients require urgent/emergent intervention. In the last decade, earlier intervention has been pursued for uncomplicated type B dissections. The INvestigation of STent-grafts in Aortic Dissection (INSTEAD) Long term (XL) study showed that there was significant crossover from medical management to Thoracic EndoVascular Aortic Repair (TEVAR) at year 3, suggesting TEVAR might benefit this population long term. Today, the application of TEVAR, which was initially designed to address aneurysmal disease, has become a standard and Food and Drug Administrative (FDA) approved management option in dissections. Currently there are four FDA approved TEVAR devices in the United States for the treatment of the thoracic dissections, namely Gore, Medtronic, Cook, and Terumo. With each iteration, there are increased opportunities for customization and widespread use in individualized patient’s pathology. As the technology improves and the feasibility of the grafts expands, the complication rates continue to decline cementing the safety and efficacy of these thoracic aortic grafts. Two rare but catastrophic complications in spinal ischemia and retrograde Stanford type A aortic dissection are further discussed. With the success of the TEVAR, a new frontier of hybrid aortic surgery has developed. The debranching of the aortic arch vessels in order to advance the TEVAR proximal landing zones has been aggressively pursued. With the widespread growth of TEVAR technology it is apparent that complex aortic pathology can be safely repaired endovascularly. Article Details

Lygus spp. are major pests of the California strawberry industry and have prompted growers to purchase and use machines called “bug vacuums” to mitigate damage throughout the production season. The...

Background Increased intestinal barrier permeability and subsequent gut microbial translocation are significant contributors to inflammatory non-AIDS comorbidities in people living with HIV (PLWH). Evidence in animal models have shown that markers of intestinal permeability and microbial translocation vary over the course of the day and are affected by food intake and circadian rhythms. However, daily variations of these markers are not characterized yet in PLWH. Herein, we assessed the variation of these markers over 24 h in PLWH receiving antiretroviral therapy (ART) in a well-controlled environment. Methods As in Canada, PLWH are predominantly men and the majority of them are now over 50 years old, we selected 11 men over 50 receiving ART with undetectable viremia for more than 3 years in this pilot study. Blood samples were collected every 4 h over 24 h before snacks/meals from 8:00 in the morning to 8:00 the next day. All participants consumed similar meals at set times, and had a comparable amount of sleep, physical exercise and light exposure. Plasma levels of bacterial lipopolysaccharide (LPS) and fungal (1→3)-β-D-Glucan (BDG) translocation markers, along with markers of intestinal damage fatty acid binding protein (I-FABP) and regenerating islet-derived protein-3α (REG3α) were assessed by ELISA or the fungitell assay. Results Participants had a median age of 57 years old (range 50 to 63). Plasma levels of BDG and REG3α did not vary significantly over the course of the study. In contrast, a significant increase of LPS was detected between 12:00 and 16:00 (Z-score: − 1.15 ± 0.18 vs 0.16 ± 0.15, p = 0.02), and between 12:00 and 24:00 (− 1.15 ± 0.18 vs 0.89 ± 0.26, p Conclusions Conversely to the fungal translocation marker BDG and the gut damage marker REG3α, time of blood collection matters for the proper evaluation for LPS and I-FABP as markers for the risk of inflammatory non-AIDS co-morbidities. These insights are instrumental for orienting clinical investigations in PLWH.

The gut microbiota is emerging as a prominent player in maintaining health through several metabolic and immune pathways. Dysregulation of gut microbiota composition, also known as dysbiosis, is involved in the clinical outcome of diabetes, inflammatory bowel diseases, cancer, aging and HIV infection. Gut dysbiosis and inflammation persist in people living with HIV (PLWH) despite receiving antiretroviral therapy, further contributing to non-AIDS comorbidities. Metformin, a widely used antidiabetic agent, has been found to benefit microbiota composition, promote gut barrier integrity and reduce inflammation in human and animal models of diabetes. Inspired by the effect of metformin on diabetes-related gut dysbiosis, we herein critically review the relevance of metformin to control inflammation in PLWH. Metformin may improve gut microbiota composition, in turn reducing inflammation and risk of non-AIDS comorbidities. This review will pave the way towards innovative strategies to counteract dysregulated microbiota and improve the lives of PLWH.

Glioblastoma is a universally lethal form of brain cancer that exhibits an array of pathophysiological phenotypes, many of which are mediated by interactions with the neuronal microenvironment1,2. Recent studies have shown that increases in neuronal activity have an important role in the proliferation and progression of glioblastoma3,4. Whether there is reciprocal crosstalk between glioblastoma and neurons remains poorly defined, as the mechanisms that underlie how these tumours remodel the neuronal milieu towards increased activity are unknown. Here, using a native mouse model of glioblastoma, we develop a high-throughput in vivo screening platform and discover several driver variants of PIK3CA. We show that tumours driven by these variants have divergent molecular properties that manifest in selective initiation of brain hyperexcitability and remodelling of the synaptic constituency. Furthermore, secreted members of the glypican (GPC) family are selectively expressed in these tumours, and GPC3 drives gliomagenesis and hyperexcitability. Together, our studies illustrate the importance of functionally interrogating diverse tumour phenotypes driven by individual, yet related, variants and reveal how glioblastoma alters the neuronal microenvironment. Glioblastoma tumours expressing oncogenic PIK3CA variants secrete the glycan GPC3, which promotes the formation of neural synapses, brain synaptic hyperexcitability and gliomagenesis.