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BACKGROUND: Irrigation is commonly used as an adjuvant treatment during the intralesional curettage of bone tumors. The goal of the present study was to analyze the in vitro cytotoxicity of commonly used irrigation solutions on chondrosarcoma and giant cell tumor (GCT) cells as there is no consensus on which solution leads to the greatest amount of cell death. METHODS: An in vitro evaluation was performed by exposing human GCT and human chondrosarcoma cell lines to 0.9% saline solution, sterile water, 70% ethanol, 3% hydrogen peroxide, 0.05% chlorhexidine gluconate (CHG), and 0.3% povidone iodine solutions independently for 2 and 5 minutes. A low-cytotoxicity control (LCC) and a high-cytotoxicity control (HCC) were established to determine the mean cytotoxicity of each solution and each solution’s superiority to LCC and non-inferiority to HCC. RESULTS: The present study demonstrated that 0.05% CHG was non-inferior to the HCC when chondrosarcoma was exposed for 5 minutes and when GCT was exposed for 2 and 5 minutes (mean cytotoxicity, 99% to 102%) (p < 0.003 for all). Sterile water was superior to the LCC when chondrosarcoma was exposed for 5 minutes and when GCT was exposed for 2 minutes (mean, 28% to 37%) (p < 0.05). Sterile water (mean, 18% to 38%) (p < 0.012) and 3% hydrogen peroxide (mean, 7% to 16%) (p < 0.001) were both inferior to the HCC. The 3 other solutions were non-superior to the LCC (mean, −24% to −5%) (p < 0.023). CONCLUSIONS: In vitro irrigation in 0.05% CHG provided high cytotoxicity, comparable with the HCC. Therefore, the use of a 0.05% CHG solution clinically could serve as a potential chemical adjuvant during intralesional curettage of chondrosarcoma and GCT. CLINICAL RELEVANCE: In an effort to reduce the burden of residual tumor cells, irrigation solutions are often utilized as adjuvant local therapy. Use of a 0.05% CHG solution clinically could serve as a potential chemical adjuvant to intralesional curettage of chondrosarcoma and GCT. Further in vivo studies may be indicated to assess clinical outcomes and safety associated with the use of 0.05% CHG in the treatment of chondrosarcoma and GCT.

AIM: International studies have shown that most colon cancers are diagnosed among people with symptoms, but research is limited in the United States. We conducted a retrospective study with adults aged 50–85 years diagnosed with stage I-IIIA colon cancer in 1995–2014 in two US healthcare systems. METHOD: Mode of detection (screening or symptomatic) was ascertained from medical records. We estimated unadjusted odds ratios (OR) and 95% confidence intervals (CI) comparing detection mode by patient factors at diagnosis (year, age, sex, race, smoking status, body mass index [BMI], Charlson score), pre-diagnostic primary care utilization, and tumor characteristics (stage, location). RESULTS: Of 1,675 people with colon cancer, 38.4% were screen-detected, while 61.6% were diagnosed following symptomatic presentation. Screen-detected cancer was more common among those diagnosed in 2010–2014 vs. 1995–1999 (OR=1.65, 95%CI=1.19–2.28), and those with a BMI of 25-0 (OR=0.71, 95%CI=0.56–0.91 for score=1, OR=0.34, 95%CI=0.26–0.45 for score=2+), and those with 2+ pre-diagnostic primary care visits (OR=0.53, 95%CI=0.37–0.76) vs. 0 visits. The odds of screen detection were lower among patients diagnosed with stage IIA (OR=0.33, 95%CI=0.27–0.41) or IIB (OR=0.12, 95%CI=0.06–0.24) cancers vs. stage I. CONCLUSION: Most colon cancers among screen-eligible adults were diagnosed following symptomatic presentation. Even with increasing screening rates over time, research is needed to better understand why specific groups are more likely to be diagnosed when symptomatic and identify opportunities for interventions.

ObjectiveLung cancer is the most common cause of cancer-related death in the USA. While most patients are diagnosed following symptomatic presentation, no studies have compared symptoms and physical examination signs at or prior to diagnosis from electronic health records (EHRs) in the USA. We aimed to identify symptoms and signs in patients prior to diagnosis in EHR data.DesignCase–control study.SettingAmbulatory care clinics at a large tertiary care academic health centre in the USA.Participants, outcomesWe studied 698 primary lung cancer cases in adults diagnosed between 1 January 2012 and 31 December 2019, and 6841 controls matched by age, sex, smoking status and type of clinic. Coded and free-text data from the EHR were extracted from 2 years prior to diagnosis date for cases and index date for controls. Univariate and multivariable conditional logistic regression were used to identify symptoms and signs associated with lung cancer at time of diagnosis, and 1, 3, 6 and 12 months before the diagnosis/index dates.ResultsEleven symptoms and signs recorded during the study period were associated with a significantly higher chance of being a lung cancer case in multivariable analyses. Of these, seven were significantly associated with lung cancer 6 months prior to diagnosis: haemoptysis (OR 3.2, 95% CI 1.9 to 5.3), cough (OR 3.1, 95% CI 2.4 to 4.0), chest crackles or wheeze (OR 3.1, 95% CI 2.3 to 4.1), bone pain (OR 2.7, 95% CI 2.1 to 3.6), back pain (OR 2.5, 95% CI 1.9 to 3.2), weight loss (OR 2.1, 95% CI 1.5 to 2.8) and fatigue (OR 1.6, 95% CI 1.3 to 2.1).ConclusionsPatients diagnosed with lung cancer appear to have symptoms and signs recorded in the EHR that distinguish them from similar matched patients in ambulatory care, often 6 months or more before diagnosis. These findings suggest opportunities to improve the diagnostic process for lung cancer.

Background Automated office blood pressure (AOBP) using 3–5 measurements taken with an oscillometric device with or without an attendant in the room may decrease “white coat” effect. We evaluated the impact of the presence or absence of the attendant and rest on BP and diagnosis of hypertension. Methods We randomly assigned 133 adults aged 18–85 with high BP at baseline (≥140/90 mm Hg), no hypertensive diagnosis and no antihypertensive medications to either attended AOBP first, unattended second, or unattended AOBP first, attended second. Outcomes included within-person BP difference for attended vs. unattended measurements; 5 vs. 15 minutes of rest; and the diagnostic performance of AOBP compared with daytime automated blood pressure measurement (ABPM). Results We found no significant differences between attended and unattended AOBP (mean difference attended − unattended [95% confidence interval, CI], systolic 0.14 mm Hg [−0.78, 1.06]; diastolic 0.16 mm Hg [−0.45, 0.78]) or by rest time (mean difference 15 − 5 minutes [95% CI], systolic −0.45 mm Hg [−1.36, 0.47]; diastolic 0.61 mm Hg [−1.23, 0.003]). AOBP was lower than mean daytime ABPM, regardless of attendance or rest (after 5 minutes rest systolic −3.6 and diastolic −2.55 mm Hg, P = 0.001 for both comparisons). Using daytime ABPM of ≥135/85 mm Hg as the diagnostic threshold, AOBP sensitivity and specificity after 5 minutes of rest were 71.0% and 54.1%, respectively. Conclusions The presence or absence of a clinic attendant during AOBP measurement and the amount of rest time before AOBP measurements had no effects on BP. AOBP measurements have low sensitivity and specificity for making a new diagnosis of hypertension.

Table of microinjected drugs

Purpose:To characterize changes in the soft-tissue sarcoma (STS) tumor immune microenvironment induced by standard neoadjuvant therapy with the goal of informing neoadjuvant immunotherapy trial design.Experimental Design:Paired pre- and postneoadjuvant therapy specimens were retrospectively identified for 32 patients with STSs and analyzed by three modalities: multiplexed IHC, NanoString, and RNA sequencing with ImmunoPrism analysis.Results:All 32 patients, representing a variety of STS histologic subtypes, received neoadjuvant radiotherapy and 21 (66%) received chemotherapy prior to radiotherapy. The most prevalent immune cells in the tumor before neoadjuvant therapy were myeloid cells (45% of all immune cells) and B cells (37%), with T (13%) and natural killer (NK) cells (5%) also present. Neoadjuvant therapy significantly increased the total immune cells infiltrating the tumors across all histologic subtypes for patients receiving neoadjuvant radiotherapy with or without chemotherapy. An increase in the percentage of monocytes and macrophages, particularly M2 macrophages, B cells, and CD4+ T cells was observed postneoadjuvant therapy. Upregulation of genes and cytokines associated with antigen presentation was also observed, and a favorable pathologic response (≥90% necrosis postneoadjuvant therapy) was associated with an increase in monocytic infiltrate. Upregulation of the T-cell checkpoint TIM3 and downregulation of OX40 were observed posttreatment.Conclusions:Standard neoadjuvant therapy induces both immunostimulatory and immunosuppressive effects within a complex sarcoma microenvironment dominated by myeloid and B cells. This work informs ongoing efforts to incorporate immune checkpoint inhibitors and novel immunotherapies into the neoadjuvant setting for STSs.

Microinjection of olaratumab does not inhibit PDGFRα, ERK, or S6 phosphorylation.

All adverse events reported on the study

Supplementary Legend

Distinct drug induced phenotypes and apoptotic responses specific to drug mechanism of action are seen at sites of CIVO microinjection.

Purpose:A persistent issue in cancer drug development is the discordance between robust antitumor drug activity observed in laboratory models and the limited benefit frequently observed when patients are treated with the same agents in clinical trials. Difficulties in accurately modeling the complexities of human tumors may underlie this problem. To address this issue, we developed Comparative In Vivo Oncology (CIVO), which enables in situ investigation of multiple microdosed drugs simultaneously in a patient's tumor. This study was designed to test CIVO's safety and feasibility in patients with soft tissue sarcoma (STS).Patients and Methods:We conducted a single arm, prospective, 13-patient pilot study. Patients scheduled for incisional biopsy or tumor resection were CIVO-injected 1 to 3 days prior to surgery. Saline or microdoses of anticancer agents were percutaneously injected into the tumor in a columnar fashion through each of eight needles. Following excision, drug responses were evaluated in the injected tissue.Results:The primary objective was met, establishing CIVO's feasibility and safety. Device-related adverse events were limited to transient grade 1 nonserious events. In addition, biomarker evaluation of localized tumor response to CIVO microinjected drugs by IHC or with NanoString GeoMx Digital Spatial Profiler demonstrated consistency with known mechanisms of action of each drug, impact on the tumor microenvironment, and historic clinical activity.Conclusions:These results are an advance toward use of CIVO as a translational research tool for early evaluation of investigational agents and drug combinations in a novel approach to phase 0 trials.See related commentary by Sleijfer and Lolkema, p. 3897

Supplementary Data from Neoadjuvant Therapy Induces a Potent Immune Response to Sarcoma, Dominated by Myeloid and B Cells

Supplementary Figure from Neoadjuvant Therapy Induces a Potent Immune Response to Sarcoma, Dominated by Myeloid and B Cells

Representative images of tumors from patients who received radiation treatment.

Device performance

Clinical Trial Design

Increased phosphorylation of PDGFR� and downstream effectors in an undifferentiated pleomorphic sarcoma displaying a lack of apoptotic response to microdosed doxorubicin.

Zirconium diboride ceramics were prepared with additions of up to 50 vol.% TiB2. The resulting (Zr,Ti)B2 ceramics formed complete solid solutions based on x-ray diffraction. The addition of TiB2 resulted in grain size decreasing from 22 μm for nominally pure ZrB2 to 7 μm for ZrB2–50 vol.% TiB2. The thermal conductivity at 25°C ranged from 93 W/m⋅K for nominally pure ZrB2 to 58 W/m⋅K for ZrB2–50 vol.% TiB2. Thermal conductivity was as high as 67 W/m⋅K for nominally pure ZrB2 at 2000°C, but dropped to 59 W/m K with the addition of 50 vol.% TiB2. Electrical resistivity measurements were used to calculate the electron contribution to thermal conductivity, which was 76 W/m⋅K for nominally pure ZrB2 decreasing to 57 W/m⋅K when 50 vol.% TiB2 was added. The phonon contribution to thermal conductivity did not change significantly for ≤10 vol.% TiB2. Additions of ≥25 vol.% TiB2 reduced the phonon contribution to nearly zero for all temperatures.

Positional information encoded in signaling molecules is essential for early patterning in the prosensory domain of the developing cochlea. The cochlea contains an exquisite repeating pattern of sensory hair cells and supporting cells. This requires precision in the morphogen signals that set the initial radial compartment boundaries, but this has not been investigated. To measure gradient formation and morphogenetic precision in developing cochlea, we developed a quantitative image analysis procedure measuring SOX2 and pSMAD1/5/9 profiles in mouse embryos at embryonic day (E)12.5, E13.5, and E14.5. Intriguingly, we found that the pSMAD1/5/9 profile forms a linear gradient in the medial ∼75% of the PSD during E12.5 and E13.5. This is a surprising activity readout for a diffusive BMP4 ligand secreted from a tightly constrained lateral region1,2 since morphogens typically form exponential or power-law gradient shapes. This is meaningful for gradient interpretation because while linear profiles offer the theoretically highest information content and distributed precision for patterning, a linear morphogen gradient has not yet been observed. In addition to the information-optimized linear profile, we found that while pSMAD1/5/9 is stable during this timeframe, an accompanying gradient of SOX2 shifts dynamically. Third, we see through joint decoding maps of pSMAD1/5/9 and SOX2 that there is a high-fidelity mapping between signaling activity and position in the regions soon to become Kölliker’s organ and the organ of Corti, where radial patterns are more intricate than lateral regions. Mapping is ambiguous in the prosensory domain precursory to the outer sulcus, where cell fates are uniform. Altogether, this research provides new insights into the precision of early morphogenetic patterning cues in the radial cochlea prosensory domain.Summary ParagraphThe organ of Corti is the precisely patterned group of cells in the cochlea responsible for transforming sound energy into our perception of hearing. Morphogenetic signals encoding positional information are crucial for the early stages of patterning along the developing cochlea’s radial axis. SOX2 and pSMAD1/5/9 are transcription factors that together serve as an integrative readout of morphogen activity during E12.5 to E14.5 in the developing mouse cochlea. However, the role of spatiotemporal precision in these signals is unknown. Here we show that pSMAD1/5/9 forms a linear profile to establish a domain spanning reference frame of positional information and that SOX2 further refines precision. We found that the pSMAD1/5/9 signal retains its linear shape across at least 24 h of development while SOX2 dynamically shifts. The stable linear pSMAD1/5/9 profile provides a global reference point of radial positional information, while the SOX2 profile improves local precision with steep slopes. Furthermore, a linear profile from a diffusive ligand is unexpected, suggesting unidentified mechanisms of BMP regulation unique to this system. A version of the source-sink model for creating a linear morphogen profile modified from its original formulation3 is explored in this system, enabling a tight fit between the BMP model and pSMAD1/5/9 data. We expect the methods and results shown here to be a starting point for increased precision in cochlear morphogen activity measurements to enable further modeling and experimental inquiry. This combination of quantitative mechanistic explanation for how signals form, along with quantitative interpretations of their decoding properties, revealing why they form a certain way, together form a potent basis for biological discovery and may even be applied to the design of synthetic systems.

ImportanceLung cancer, the US’s leading cause of cancer death, is often diagnosed following presentation to health care settings with symptoms, and many patients present with late-stage disease.ObjectiveTo investigate the association between weight loss and subsequent diagnosis of incident lung cancer in an ambulatory care population and to assess whether recorded weight change had higher odds of lung cancer diagnosis than objective measurements.Design, Setting, and ParticipantsThis case-control study included patients visiting a US academic medical center between January 1, 2012, and December 31, 2019. Data were derived from US ambulatory care electronic health records from the University of Washington Medical Center linked to the local Surveillance, Epidemiology, and End Results cancer registry. Cases were identified from patients who had a primary lung cancer diagnosis between 2012 and 2019; controls were matched on age, sex, smoking status, and presenting to the same type of ambulatory clinic as cases. Data were analyzed from March 2022 through January 2023.ExposureContinuous and categorical weight change were assessed.Main Outcomes and MeasuresOdds ratios estimating the likelihood of a diagnosis of lung cancer were calculated using univariable and multivariable conditional logistic regression.ResultsA total of 625 patients aged 40 years or older with a first primary lung cancer diagnosis and 4606 matched controls were included (1915 [36.6%] ages 60 to 69 years; 418 [8.0%] Asian, 389 [7.4%] Black, 4092 [78.2%] White). In unadjusted analyses, participants with weight loss of 1% to 3% (odds ratio [OR], 1.12; 95% CI, 0.88-1.41), 3% to 5% (OR, 1.36; 95% CI, 0.99-1.88), or 5% to 10% (OR, 1.23; 95% CI, 0.82-1.85) over a 2-year period did not have statistically significantly increased risk of lung cancer diagnosis compared with those who maintained a steady weight. However, participants with weight loss of 10% to 50% had more than twice the odds of a lung cancer diagnosis (OR, 2.27; 95% CI, 1.27-4.05). Most categories of weight loss showed significant associations with an increased risk of lung cancer diagnosis for at least 6 months prior to diagnosis. Patients who had weight loss both recorded in clinicians’ notes and measured had higher odds of lung cancer compared with patients who had only recorded (OR, 1.26; odds; 95% CI, 1.04-1.52) or measured (OR, 8.53; 95% CI, 6.99-10.40) weight loss.Conclusions and RelevanceIn this case-control study, weight loss in the prior 6 months was associated with incident lung cancer diagnosis and was present whether weight loss was recorded as a symptom by the clinician or based on changes in routinely measured weight, demonstrating a potential opportunity for early diagnosis. The association between measured and recorded weight loss by clinicians presents novel results for the US.

Purpose: To characterize changes in the soft-tissue sarcoma (STS) tumor immune microenvironment induced by standard neoadjuvant therapy with the goal of informing neoadjuvant immunotherapy trial design. Experimental Design: Paired pre- and postneoadjuvant therapy specimens were retrospectively identified for 32 patients with STSs and analyzed by three modalities: multiplexed IHC, NanoString, and RNA sequencing with ImmunoPrism analysis. Results: All 32 patients, representing a variety of STS histologic subtypes, received neoadjuvant radiotherapy and 21 (66%) received chemotherapy prior to radiotherapy. The most prevalent immune cells in the tumor before neoadjuvant therapy were myeloid cells (45% of all immune cells) and B cells (37%), with T (13%) and natural killer (NK) cells (5%) also present. Neoadjuvant therapy significantly increased the total immune cells infiltrating the tumors across all histologic subtypes for patients receiving neoadjuvant radiotherapy with or without chemotherapy. An increase in the percentage of monocytes and macrophages, particularly M2 macrophages, B cells, and CD4+ T cells was observed postneoadjuvant therapy. Upregulation of genes and cytokines associated with antigen presentation was also observed, and a favorable pathologic response (≥90% necrosis postneoadjuvant therapy) was associated with an increase in monocytic infiltrate. Upregulation of the T-cell checkpoint TIM3 and downregulation of OX40 were observed posttreatment. Conclusions: Standard neoadjuvant therapy induces both immunostimulatory and immunosuppressive effects within a complex sarcoma microenvironment dominated by myeloid and B cells. This work informs ongoing efforts to incorporate immune checkpoint inhibitors and novel immunotherapies into the neoadjuvant setting for STSs.

Background: Extraskeletal myxoid chondrosarcoma (EMCS) is a rare tumor that typically has an indolent course but high rate of recurrence. We queried the Surveillance, Epidemiology, and End Results (SEER) database to assess factors associated with metastasis, treatment, and survival. Methods: We queried the SEER 1973–2016 database for patients with myxoid chondrosarcoma (ICD-O-3: 9231/3). Kaplan–Meier analyses and Cox proportional hazard models assessed effects on overall survival (OS) of demographics and clinical characteristics. Logistic regression assessed associations between tumor location and distant disease. Primary analysis was a complete case analysis; multiple imputation (MI) was used in a sensitivity analysis. Results: Locoregional disease (LRD) was found in 373 (85%) of patients. In univariate analysis with LRD, surgery correlated with superior OS [HR = 0.27; 95% confidence interval (CI), 0.16–0.47]; chemotherapy and radiotherapy associated with inferior OS (HR = 1.90; 95% CI, 1.11–3.27 and HR = 1.45; 95% CI, 1.03–2.06, respectively). No treatment modality associated with OS in the adjusted, complete case model. In the adjusted sensitivity analysis, surgery associated with superior outcomes (HR = 0.36; 95% CI, 0.19–0.69). There was no OS difference by primary tumor site. 10-year OS with distant disease was 10% (95% CI, 2%–25%). Conclusions: Surgery in LRD associated with improved OS in univariate analysis and adjusted models correcting for missing data. There was no OS benefit with chemotherapy or radiotherapy. Impact: This represents the largest report of EMCS with long-term follow-up. Despite the reputedly indolent nature of EMCS, outcomes with metastatic disease are poor. We provide OS benchmarks and guidance for stratification in future prospective trials.

Purpose: A persistent issue in cancer drug development is the discordance between robust antitumor drug activity observed in laboratory models and the limited benefit frequently observed when patients are treated with the same agents in clinical trials. Difficulties in accurately modeling the complexities of human tumors may underlie this problem. To address this issue, we developed Comparative In Vivo Oncology (CIVO), which enables in situ investigation of multiple microdosed drugs simultaneously in a patient's tumor. This study was designed to test CIVO's safety and feasibility in patients with soft tissue sarcoma (STS). Patients and Methods: We conducted a single arm, prospective, 13-patient pilot study. Patients scheduled for incisional biopsy or tumor resection were CIVO-injected 1 to 3 days prior to surgery. Saline or microdoses of anticancer agents were percutaneously injected into the tumor in a columnar fashion through each of eight needles. Following excision, drug responses were evaluated in the injected tissue. Results: The primary objective was met, establishing CIVO's feasibility and safety. Device-related adverse events were limited to transient grade 1 nonserious events. In addition, biomarker evaluation of localized tumor response to CIVO microinjected drugs by IHC or with NanoString GeoMx Digital Spatial Profiler demonstrated consistency with known mechanisms of action of each drug, impact on the tumor microenvironment, and historic clinical activity. Conclusions: These results are an advance toward use of CIVO as a translational research tool for early evaluation of investigational agents and drug combinations in a novel approach to phase 0 trials. See related commentary by Sleijfer and Lolkema, p. 3897

Objectives: Factors associated with nodal involvement in chondrosarcoma and outcomes based on treatment modality were analyzed using the Surveillance, Epidemiology, and End Results (SEER) database. Methods: Chondrosarcomas involving axial and appendicular parts of the body diagnosed from 2004 to 2015 were identified in SEER. Clinical, pathologic, and treatment parameters were compared with respect to nodal status at initial diagnosis by Fisher’s exact or Student’s t-test. Disease-specific survival (DSS) and overall survival (OS) were evaluated by Kaplan-Meier analyses, and by Cox regression models. Results: Synchronous regional nodal metastases were present in 1.3% of chondrosarcoma patients. Lymph node involvement was associated with primary tumor location in extraskeletal tissue and the pelvis, and with distant metastasis and larger primary tumor size at diagnosis. Patients with nodal involvement had 5-year DSS of 48% [95% confidence interval (CI): 28%–65%], versus 82% (95%CI: 80%–84%) for those without (log-rank P Conclusions: The nodal disease is uncommon at presentation in chondrosarcoma. Greater clinical vigilance for regional nodal metastases may be warranted for those with specific risk factors, including extraskeletal or pelvic primary sites, myxoid, mesenchymal, or dedifferentiated histologies, and large size. Surgical excision of regional nodes is associated with improvedDSS/OS. This analysis suggests a therapeutic effect of surgical treatment, rather than selection for favorable underlying biological factors.

Home testing for infectious disease has come to the forefront during the COVID-19 pandemic. There is now considerable commercial interest in developing complete home tests for a variety of viral and bacterial pathogens. However, the regulatory science around home infectious disease test approval and procedures that test manufacturers and laboratory professionals will need to follow have not yet been formalized by the U.S. Food and Drug Administration (FDA), with the exception of Emergency Use Authorization (EUA) guidance for COVID-19 tests. We describe the state of home-based testing for influenza with a focus on sample-to-result home tests, discuss the various regulatory pathways by which these products can reach populations, and provide recommendations for study designs, patient samples, and other important features necessary to gain market access. These recommendations have potential application for home use tests being developed for other viral respiratory infections, such as COVID-19, as guidance moves from EUA designation into 510(k) requirements.

Home-based testing for COVID-19 has potential to reduce existing health care disparities among underserved populations in the United States. However, implementation of home-based tests in these communities may face significant barriers. This study evaluates the acceptability, feasibility, and success of home-based testing and the potential added benefit of active support from trusted community health workers for Native Americans and Hispanic/Latino adults living in rural Montana and Washington states.The academic-community research team designed the trial to be responsive to community needs for understanding barriers and supports to home-based COVID-19 testing. The "Protecting Our Community" study is a two-arm pragmatic randomized controlled trial in which a total of 400 participants are randomized to active or passive arms. Participants of both study arms receive a commercially available home collection COVID-19 test kit, which is completed by mailing a self-collected nasal swab to a central laboratory. The primary study outcome is return of the kit to the central lab within 14 days. The cultural, social, behavioral, and economic barriers to home-based COVID-19 testing are also assessed by qualitative research methods. A survey and semi-structured interviews are conducted after the trial to evaluate perceptions and experience of home-based testing.Implementing home-based testing in underserved populations, including among Native American and Hispanic/Latino communities, may require additional support to be successful. The Protecting Our Community trial examines the effect of trusted community health workers on use of home-based testing, which may be adaptable for community-driven models of home-based testing in other underserved populations.

Background The local treatment of extremity sarcomas usually is predicated on a decision between limb salvage and amputation. The manner in which surgical options are presented in the context of shared decision-making may influence this decision. In a population of "simulated" patients-survey respondents presented with a mock clinical vignette and then asked to choose between treatments-we assessed cognitive bias by deliberate alteration of the subjective presentation of the same objective information. Questions/purposes (1) Will the manner in which information is presented to a simulated patient, in the setting of treatment for a bone sarcoma, bias their decision regarding pursuing amputation versus limb salvage? (2) At the time of decision-making, will a simulated patient's personal background, demographics, or mood affect their ultimate decision? Methods Survey respondents (Amazon MTurk platform) were presented with mock clinical vignettes simulating a sarcoma diagnosis and were asked to choose between amputation and limb salvage. Specific iterations were designed to assess several described types of cognitive bias. These scenarios were distributed, using anonymous online surveys, to potential participants aged 18 years or older. Recruitment was geographically restricted to individuals in the United States. Overall, 404 respondents completed the survey. The average age of respondents was 33 years (SD 1.2 years), 60% were male and 40% were female. In all, 12% of respondents worked in healthcare. Each respondent also completed questions regarding his or her demographics and his or her current mood. Associations between the type of bias presented and the respondent's choice of limb salvage versus amputation were examined. Independent sample t-tests were used to compare means. Statistical significance was defined as p Results When amputation was presented as an option to mitigate functional loss (framing bias), more patients chose it than when limb salvage was presented as means for increased functional gains (23% [23 of 100] versus 10% [12 of 118], odds ratio [OR], 2.26; p = 0.010). Older simulated patients were more likely to choose limb salvage when exposed to framing bias versus younger patients (mean age 33 years versus 30 years, p = 0.02). Respondents who were employed in healthcare more commonly chose amputation versus limb salvage when exposed to framing bias (24% [eight of 35] versus 9% [17 of 183]; OR, 2.46; p = 0.02). Those who chose amputation were more likely to score higher on scales that measured depression or negative affect. Conclusions Shared decision-making in orthopaedic oncology represents a unique circumstance in which several variables may influence a patient's decision between limb salvage and amputation. Invoking cognitive bias in simulated patients appeared to affect treatment decisions. We cannot be sure that these findings translate to the experience of actual sarcoma patients; however, we can conclude that important treatment decisions may be affected by cognitive bias and that patient characteristics (in this study, age, healthcare profession, and mood) may be associated with an individual's susceptibility to cognitive bias. We hope these observations will assist providers in the thoughtful delivery of highly charged information to patients facing difficult decisions, and promote further study of this important concept. Level of evidence Level III, economic and decision analyses.

Background Sore throat is a common condition associated with a high rate of antibiotic prescriptions, despite limited evidence for the effectiveness of antibiotics. Corticosteroids may improve symptoms of sore throat by reducing inflammation of the upper respiratory tract. This review is an update to our review published in 2012. Objectives To assess the clinical benefit and safety of corticosteroids in reducing the symptoms of sore throat in adults and children. Search methods We searched CENTRAL (Issue 4, 2019), MEDLINE (1966 to 14 May 2019), Embase (1974 to 14 May 2019), the Database of Abstracts of Reviews of Effects (DARE, 2002 to 2015), and the NHS Economic Evaluation Database (inception to 2015). We also searched the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) and ClinicalTrials.gov. Selection criteria We included randomised controlled trials (RCTs) that compared steroids to either placebo or standard care in adults and children (aged over three years) with sore throat. We excluded studies of hospitalised participants, those with infectious mononucleosis (glandular fever), sore throat following tonsillectomy or intubation, or peritonsillar abscess. Data collection and analysis We used standard methodological procedures expected by Cochrane. Main results We included one new RCT in this update, for a total of nine trials involving 1319 participants (369 children and 950 adults). In eight trials, participants in both corticosteroid and placebo groups received antibiotics; one trial offered delayed prescription of antibiotics based on clinical assessment. Only two trials reported funding sources (government and a university foundation). In addition to any effect of antibiotics and analgesia, corticosteroids increased the likelihood of complete resolution of pain at 24 hours by 2.40 times (risk ratio (RR) 2.4, 95% confidence interval (CI) 1.29 to 4.47; P = 0.006; I² = 67%; high‐certainty evidence) and at 48 hours by 1.5 times (RR 1.50, 95% CI 1.27 to 1.76; P < 0.001; I² = 0%; high‐certainty evidence). Five people need to be treated to prevent one person continuing to experience pain at 24 hours. Corticosteroids also reduced the mean time to onset of pain relief and the mean time to complete resolution of pain by 6 and 11.6 hours, respectively, although significant heterogeneity was present (moderate‐certainty evidence). At 24 hours, pain (assessed by visual analogue scales) was reduced by an additional 10.6% by corticosteroids (moderate‐certainty evidence). No differences were reported in recurrence/relapse rates, days missed from work or school, or adverse events for participants taking corticosteroids compared to placebo. However, the reporting of adverse events was poor, and only two trials included children or reported days missed from work or school. The included studies were assessed as moderate quality evidence, but the small number of included studies has the potential to increase the uncertainty, particularly in terms of applying these results to children. Authors' conclusions Oral or intramuscular corticosteroids, in addition to antibiotics, moderately increased the likelihood of both resolution and improvement of pain in participants with sore throat. Given the limited benefit, further research into the harms and benefits of short courses of steroids is needed to permit informed decision‐making.

BACKGROUND Rapid diagnostic tests (RDTs) for influenza used by individuals at home could potentially expand access to testing and reduce the impact of influenza on health systems. Improving access to testing could lead to earlier diagnosis following symptom onset, allowing more rapid interventions for those who test positive, including behavioral changes to minimize spread. However, the accuracy of RDTs for influenza has not been determined in self-testing populations. OBJECTIVE This study aims to assess the accuracy of an influenza RDT conducted at home by lay users with acute respiratory illness compared with that of a self-collected sample by the same individual mailed to a laboratory for reference testing. METHODS We conducted a comparative accuracy study of an at-home influenza RDT (Ellume) in a convenience sample of individuals experiencing acute respiratory illness symptoms. Participants were enrolled in February and March 2020 from the Greater Seattle region in Washington, United States. Participants were mailed the influenza RDT and reference sample collection materials, which they completed and returned for quantitative reverse-transcription polymerase chain reaction influenza testing in a central laboratory. We explored the impact of age, influenza type, duration, and severity of symptoms on RDT accuracy and on cycle threshold for influenza virus and ribonuclease P, a marker of human DNA. RESULTS A total of 605 participants completed all study steps and were included in our analysis, of whom 87 (14.4%) tested positive for influenza by quantitative reverse-transcription polymerase chain reaction (70/87, 80% for influenza A and 17/87, 20% for influenza B). The overall sensitivity and specificity of the RDT compared with the reference test were 61% (95% CI 50%-71%) and 95% (95% CI 93%-97%), respectively. Among individuals with symptom onset ≤72 hours, sensitivity was 63% (95% CI 48%-76%) and specificity was 94% (95% CI 91%-97%), whereas, for those with duration >72 hours, sensitivity and specificity were 58% (95% CI 41%-74%) and 96% (95% CI 93%-98%), respectively. Viral load on reference swabs was negatively correlated with symptom onset, and quantities of the endogenous marker gene ribonuclease P did not differ among reference standard positive and negative groups, age groups, or influenza subtypes. The RDT did not have higher sensitivity or specificity among those who reported more severe illnesses. CONCLUSIONS The sensitivity and specificity of the self-test were comparable with those of influenza RDTs used in clinical settings. False-negative self-test results were more common when the test was used after 72 hours of symptom onset but were not related to inadequate swab collection or severity of illness. Therefore, the deployment of home tests may provide a valuable tool to support the management of influenza and other respiratory infections.