Assessment and comparison of the ILI case definition in clinical and school-based community settings: ORCHARDS/IISP.

Context: Influenza-like illness (ILI) is commonly used in clinical and public health settings to identify influenza cases. CDC defines ILI as fever and either cough or sore throat, with symptom onset within 7 days. Objective: Assess performance of ILI criteria in two settings (clinical and community), comparing symptom profiles and laboratory detection of influenza in children. Study Design and Analysis: Retrospective analyses of data from medically attended influenza (MAI) surveillance and a communitybased study. Datasets were analyzed separately to assess predictors of influenza cases. Analyses were limited to specimens collected within 7 days of symptom onset. Relationships between influenza and each categorical variable were described by the confusion matrix, sensitivity, and specificity. Associations were tested using chi-square tests. Unadjusted and adjusted logistic regression models were used for all variables with RT-PCR result as the outcome. Setting or Dataset: The ORegon CHild Absenteeism due to Respiratory Disease Study (ORCHARDS) is a respiratory infection study based in the Oregon School District (Dane County, WI). The Wisconsin Influenza Incidence Surveillance Project (IISP) is a MAI surveillance system operating in five family medicine clinics in Dane County. Population Studied: Children aged 4-18 years with acute respiratory infections. Intervention/Instrument: Oropharyngeal specimens, collected by research staff (ORCHARDS) or clinicians (IISP), were tested for influenza via RT-PCR and for multiple respiratory viruses at the Wisconsin State Laboratory of Hygiene. Extensive demographic and symptoms data were collected from all participants. Outcome Measures: Influenza(+)PCR. Results: From 9/7/2010-3/12/2020, 1,338 and 2,359 specimens meeting inclusion criteria were collected for IISP and ORCHARDS, respectively. Cough, fever, and ILI classification were significantly associated with influenza (sensitivity ≥92.8%, ≥85.9%, and ≥84.5%, respectively). Receiver operator curve analysis confirmed ILI had high predictive ability in both settings, improved by the inclusion of seasonality and influenza vaccination status (IISP: 0.61 vs 0.76, ORCHARDS: 0.68 vs 0.78). Conclusions: ILI performed well in both clinical and community contexts. Factors most highly associated with increased odds of RT-PCR(+) results were cough, fever, and ILI. Inclusion of seasonality and influenza vaccination status improved the predictive value of ILI in both datasets.

Association of Fentanyl Test Strip Use, Perceived Overdose Risk, and Naloxone Possession among People Who Use Drugs.

Background: As opioid overdoses continue rising, interventions are needed to expand naloxone carriage, an opioid overdose reversal agent. Use of fentanyl test strips (FTS) might promote naloxone carriage. This study examines the relationship between FTS use, perceived overdose risk, and naloxone carriage in Wisconsin, United States. Methods: In a survey of people who use drugs (n = 341) in southern Wisconsin, respondents were asked about FTS use, perceived overdose risk, and how often they (1) have naloxone, (2) have more than one dose of naloxone, and (3) the number of naloxone doses possessed currently. Likert responses were mapped to an integer scale. Ordinal and linear multivariable regression examined the relationship between FTS use and study outcomes while adjusting for respondent characteristics. Results: Most respondents were male (59.6%), identified heroin as their drug of choice (70.7%) and reported intravenous use (87.9%). In unadjusted models, FTS use was associated with more often having naloxone (OR: 2.10; p = 0.005), more often having multiple naloxone doses (OR: 2.98; p < 0.001), and possessing a greater number of naloxone doses (dose count difference: 2.85; p = 0.001). In adjusted models, FTS use was associated with more often having multiple naloxone doses (OR: 2.29; p = 0.005) and possessing a greater number of naloxone doses (dose count difference: 2.25, p = 0.020). Conclusions: Individuals who use FTS more often carry multiple doses relative to individuals who do not use FTS. Given that naloxone carriage is critical for reducing opioid overdose risk, expanding FTS use may offer a strategy to reduce opioid overdose rates via improved naloxone carriage.

Factors impacting the efficacy of the in-situ vaccine with CpG and OX40 agonist.

BACKGROUND: The in-situ vaccine using CpG oligodeoxynucleotide combined with OX40 agonist antibody (CpG + OX40) has been shown to be an effective therapy activating an anti-tumor T cell response in certain settings. The roles of tumor volume, tumor model, and the addition of checkpoint blockade in the efficacy of CpG + OX40 in-situ vaccination remains unknown. METHODS: Mice bearing flank tumors (B78 melanoma or A20 lymphoma) were treated with combinations of CpG, OX40, and anti-CTLA-4. Tumor growth and survival were monitored. In vivo T cell depletion, tumor cell phenotype, and tumor infiltrating lymphocyte (TIL) studies were performed. Tumor cell sensitivity to CpG and macrophages were evaluated in vitro. RESULTS: As tumor volumes increased in the B78 (one-tumor) and A20 (one-tumor or two-tumor) models, the anti-tumor efficacy of the in-situ vaccine decreased. In vitro, CpG had a direct effect on A20 proliferation and phenotype and an indirect effect on B78 proliferation via macrophage activation. As A20 tumors progressed in vivo, tumor cell phenotype changed, and T cells became more involved in the local CpG + OX40 mediated anti-tumor response. In mice with larger tumors that were poorly responsive to CpG + OX40, the addition of anti-CTLA-4 enhanced the anti-tumor efficacy in the A20 but not B78 models. CONCLUSIONS: Increased tumor volume negatively impacts the anti-tumor capability of CpG + OX40 in-situ vaccine. The addition of checkpoint blockade augmented the efficacy of CpG + OX40 in the A20 but not B78 model. These results highlight the importance of considering multiple preclinical model conditions when assessing the efficacy of cancer immunotherapy regimens and their translation to clinical testing.

Differences in drug use behaviors that impact overdose risk among individuals who do and do not use fentanyl test strips for drug checking.

BACKGROUND: Opioid-involved overdose continues to rise, largely explained by fentanyl adulteration of the illicit opioid supply. Fentanyl test strips are a novel drug checking tool that can be used by people who use drugs to detect the presence of fentanyl in drug products. However, it is unclear whether fentanyl test strip use can prompt behavior changes that impact risk of overdose. METHODS: In this mixed-methods study involving a structured survey (n = 341) of syringe service program clients in southern Wisconsin, we examined the association between fentanyl test strip use and overdose risk behaviors in scenarios where the presence of fentanyl is confirmed and unknown. Individual items were transformed into summary scales representing the performance of riskier and safer behaviors. Linear regression examined the association of behaviors with FTS use. Models are adjusted for study site, race/ethnicity, age, gender, drug of choice, indicator of polysubstance use, times used per day, and lifetime overdose count. RESULTS: In response to survey questions before prompting about fentanyl risk, people who used fentanyl test strips reported an increased number of safer (p = 0.001) as well as riskier behaviors (p = 0.018) relative to people who did not use fentanyl test strips. The same held true in situations when fentanyl adulteration was suspected, though fentanyl test strip use lost significance in the fully adjusted model examining safer behaviors (safer: p = 0.143; riskier: p = 0.004). Among people who use fentanyl test strips, in unadjusted models, a positive test result was associated with more safer behaviors and fewer riskier behaviors, but these associations became nonsignificant in fully adjusted models (safer: p = 0.998; riskier: p = 0.171). Loss of significance was largely due to the addition of either polysubstance use or age to the model. CONCLUSIONS: Fentanyl test strip use is associated with behaviors that may impact overdose risk, including safer and riskier behaviors. Specifically, a positive test result may promote more risk reducing behaviors and fewer risk enhancing behaviors than a negative test result. Results suggest that while FTS may promote safer drug use behaviors, outreach and education should emphasize the need for multiple harm reduction techniques in all scenarios.

Exploring Expressive Writing with Patients With Chronic Pain During Primary Care Visits.

BACKGROUND: Patients living with chronic pain may feel frustrated with and neglected by clinicians who care for them, leading to negative health care experiences. Clinicians may struggle to find new ways to engage and connect with patients experiencing chronic pain. Both patients and clinicians may benefit from expressive writing by potentially improving communication and creating a deeper sense of connection within medical visits. METHODS: An expressive writing activity, the Three-Minute Mental Makeover (3MMM), was conducted with 15 patients living with chronic pain during primary care visits with 5 UW Health family medicine physicians. Patient and physician experience using the 3MMM was measured using pre- and post-visit surveys and individual interviews. RESULTS: Both physicians and patients viewed the experience of doing the 3MMM together positively. We identified 8 key themes from individual follow-up interviews with patients and physicians: (1) opening the door, (2) insight into the doctor/patient as a person, (3) peer-to-peer communication, (4) closeness and connection, (5) comfort and relaxation, (6) unexpected learning, (7) unexpected value to patients, and (8) vulnerability and self-disclosure. The most commonly reported barriers to physicians using the activity in practice were lack of time and persuading other physicians to do the activity. DSICUSSION: Patients with chronic pain and the clinicians who care for them may benefit from an expressive writing exercise, such as the 3MMM, in the key realms of building relationships, communication, and trust.

A combined radio-immunotherapy regimen eradicates late-stage tumors in mice.

Background: The majority of experimental approaches for cancer immunotherapy are tested against relatively small tumors in tumor-bearing mice, because in most cases advanced cancers are resistant to the treatments. In this study, we asked if even late-stage mouse tumors can be eradicated by a rationally designed combined radio-immunotherapy (CRI) regimen. Methods: CRI consisted of local radiotherapy, intratumoral IL-12, slow-release systemic IL-2 and anti- CTLA-4 antibody. Therapeutic effects of CRI against several weakly immunogenic and immunogenic mouse tumors including B78 melanoma, MC38 and CT26 colon carcinomas and 9464D neuroblastoma were evaluated. Immune cell depletion and flow cytometric analysis were performed to determine the mechanisms of the antitumor effects. Results: Tumors with volumes of 2,000 mm3 or larger were eradicated by CRI. Flow analyses of the tumors revealed reduction of T regulatory (Treg) cells and increase of CD8/Treg ratios following CRI. Rapid shrinkage of the treated tumors did not require T cells, whereas T cells were involved in the systemic effect against the distant tumors. Cured mice developed immunological memory. Conclusions: These findings underscore that rationally designed combination immunotherapy regimens can be effective even against large, late-stage tumors.

Assessing the Impact of a Serious Game (MedSMARxT: Adventures in PharmaCity) in Improving Opioid Safety Awareness Among Adolescents and Parents: Quantitative Study.

BACKGROUND: The opioid crisis continues to worsen across the United States, affecting people of all demographics. Few evidence-based interventions exist for educating families, particularly those with adolescents, about opioid prescription safety. Serious games have demonstrated impacts in improving medication-related outcomes for various health conditions. The characterizing goal of this serious game is to improve opioid safety knowledge and awareness among adolescents and their families. OBJECTIVE: This study evaluated the impact of a serious game, MedSMARxT: Adventures in PharmaCity, designed to foster opioid safety awareness among adolescents and their parents. METHODS: A national sample of parents and their adolescent children was recruited through Qualtrics research panels, social media, listservs, and snowball sampling. Eligible participants were adolescents aged between 12 and 18 years and their parents. Study participants were required to reside in the United States; speak, read, and understand English; and have access to a computer with a webcam. Parent-child dyads completed pregame and postgame surveys and participated in gameplay for up to 30 minutes. Primary outcome scales have been previously evaluated by the study team. RESULTS: A total of 60 adolescent participants and 68 parent participants met full attention criteria for inclusion in this study. Statistical analysis confirmed that both adolescents' and parents' concept scores improved from baseline regarding opioid safety self-efficacy (adolescent: mean 0.35, SD 0.60; P<.001; parent: mean 0.28, SD 0.42; P<.001), perceived knowledge (adolescent: mean 1.08, SD 1.04; P<.001; parent: mean 0.56, SD 0.55; P<.001), behavioral intent (adolescent: mean 0.26, SD 0.39; P<.001; parent: mean 0.25, SD 0.32; P<.001), safe storage (adolescent: mean 0.12, SD 0.27; P<.001; parent: mean 0.03, SD 0.11; P=.03), disposal knowledge (adolescent: mean 0.10, SD 0.27; P=.006; parent: mean 0.07, SD 0.16; P<.001), and knowledge about misuse behavior (adolescent: mean 0.05, SD 0.14; P=.002; parent: mean 0.04, SD 0.10; P<.001). Participant groups, stratified by who completed and who did not complete gameplay, improved their knowledge and awareness, with no significant differences between subgroups. CONCLUSIONS: The use of this serious game to improve opioid prescription safety practices among parents and adolescents was supported by the study findings. MedSMARxT: Adventures in PharmaCity is an intervention with the capability of teaching parents and adolescents about safe opioid prescription practices. Further studies and game refinement are needed to demonstrate the effectiveness of a game-based intervention in clinical settings and community pharmacies.

A Systematic Review and Pooled Analysis of Hypothesized versus Observed Effect Sizes in Early Phase Cancer Prevention Clinical Trials.

Early phase cancer prevention trials are designed to demonstrate safety, tolerability, feasibility, and signals of efficacy of preventive agents. Yet it is often observed that many trials fail to detect intervention effects. We conducted a systematic review and pooled analyses of recently completed early phase chemoprevention trials to gain in depth insight on the failure of detecting efficacy signals by comparing hypothesized effect sizes to the corresponding observed effect sizes.Single- or multi-arm efficacy chemoprevention trials conducted under the phase 0/I/II Cancer Prevention Clinical Trials Program of the Division of Cancer Prevention, NCI between 2003 and 2019 were evaluated. A total of 59 chemoprevention trials were reviewed. Twenty-four studies were efficacy or biomarker trials with complete information on hypothesized and observed effect sizes and included in this analysis. The majority of the trials (n = 18) were multi-arm randomized studies of which 15 trials were blinded. The pooled estimate of the observed to hypothesized effect size ratio was 0.57 (95% confidence interval: 0.42-0.73, P < 0.001) based on a random-effects model. There were no significant differences detected in the ratio of observed to hypothesized effect sizes when conducting various subgroup analyses.The results demonstrate that the majority of early phase cancer chemoprevention trials have substantially smaller observed effect sizes than hypothesized effect sizes. Sample size calculations for early phase chemoprevention trials need to balance the potential detectable effect sizes with realistic and cost-effective accrual of study populations, thereby, detecting only intervention effects large enough to justify subsequent large-scale confirmatory trials. PREVENTION RELEVANCE: The results of this systematic review and pooled analyses demonstrate that for early chemoprevention trials, there are substantial differences between hypothesized and observed effect sizes, regardless of study characteristics. The conduct of early phase chemoprevention trial requires careful planning of study design, primary endpoint, and sample size determination.

Cyclophosphamide augments the efficacy of in situ vaccination in a mouse melanoma model.

Introduction: We have previously shown that an intratumoral (IT) injection of the hu14.18-IL2 immunocytokine (IC), an anti-GD2 antibody linked to interleukin 2, can serve as an in situ vaccine and synergize with local radiotherapy (RT) to induce T cell-mediated antitumor effects. We hypothesized that cyclophosphamide (CY), a chemotherapeutic agent capable of depleting T regulatory cells (Tregs), would augment in situ vaccination. GD2+ B78 mouse melanoma cells were injected intradermally in syngeneic C57BL/6 mice. Methods: Treatments with RT (12Gy) and/or CY (100 mg/kg i.p.) started when tumors reached 100-300 mm3 (day 0 of treatment), followed by five daily injections of IT-IC (25 mcg) on days 5-9. Tumor growth and survival were followed. In addition, tumors were analyzed by flow cytometry. Results: Similar to RT, CY enhanced the antitumor effect of IC. The strongest antitumor effect was achieved when CY, RT and IC were combined, as compared to combinations of IC+RT or IC+CY. Flow cytometric analyses showed that the combined treatment with CY, RT and IC decreased Tregs and increased the ratio of CD8+ cells/Tregs within the tumors. Moreover, in mice bearing two separate tumors, the combination of RT and IT-IC delivered to one tumor, together with systemic CY, led to a systemic antitumor effect detected as shrinkage of the tumor not treated directly with RT and IT-IC. Cured mice developed immunological memory as they were able to reject B78 tumor rechallenge. Conclusion: Taken together, these preclinical results show that CY can augment the antitumor efficacy of IT- IC, given alone or in combination with local RT, suggesting potential benefit in clinical testing of these combinations.