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Oncology patients presenting for outpatient evaluation of a respiratory tract infection (RTI) are often tested for a variety of viruses with a respiratory pathogen panel (RPP) in addition to influenza and SARS-CoV-2. This triad of testing is expensive and uncomfortable because it requires 2 nasal swabs. Little evidence supports the use of an RPP in outpatient settings, but it is routinely ordered. This retrospective chart review analyzed 183 RPPs performed at Jefferson between April 2020 and November 2021 in outpatient oncology patients presenting with RTI. Data collected included patient demographics, symptoms, and exam findings at time of RPP, additional testing completed, results of RPP, antibiotic and antiviral use before and after RPP results, and patient outcomes 30 days after RPP. Descriptive statistics were calculated. Of the 183 RPPs analyzed, 16.9% (31) were positive for at least 1 respiratory virus. Fifty-two patients (28.4%) started antibiotics before results of the RPP. Of those, 2 patients (3.8%) had a change in antibiotic plan after RPP results returned. Zero patients were started on antiviral medication before results of the RPP. One patient started antiviral treatment after RPP results returned. In total, only 3 patients (1.6%) had an RPP-driven change in medication management. This study suggests limited utility in use of RPPs for oncology patients presenting to the office with RTI symptoms. Targeted testing with a single nasal swab for influenza, RSV, and SARS-CoV-2 may be more clinically relevant. The authors hope to use these data to implement a quality improvement initiative to reduce RPP utilization in this population.

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Introduction. Intestinal helminths and microbiota share the same anatomical niche during infection and are likely to interact either directly or indirectly. Whether intestinal helminths employ bactericidal strategies that influence their microbial environment is not completely understood.Hypothesis. In the present study, the hypothesis that the adult hookworm Nippostrongylus brasiliensis produces molecules that impair bacterial growth in vitro, is tested.Aim. To investigate the in vitro bactericidal activity of Nippostrongylus brasiliensis against commensal and pathogenic bacteria.Methodology. The bactericidal effect of somatic extract and excretory-secretory products of adult Nippostrongylus brasiliensis on Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli, Salmonella enterica serovar Typhimurium, and Klebsiella pneumoniae) bacteria was assessed using growth assays. Minimum inhibitory concentration and minimum bactericidal concentration assays were performed using excretory-secretory products released from the pathogen.Results. Broad-spectrum in vitro bactericidal activity in excretory-secretory products, but not somatic extract of adult Nippostrongylus brasiliensis was detected. The bactericidal activity of excretory-secretory products was concentration-dependent, maintained after heat treatment, and preserved after repeated freezing and thawing.Conclusion. The results of this study demonstrate that helminths such as Nippostrongylus brasiliensis release molecules via their excretory-secretory pathway that have broad-spectrum bactericidal activity. The mechanisms responsible for this bactericidal activity remain to be determined and further studies aimed at isolating and identifying active bactericidal molecules are needed.

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Luteolin (LUT) is a flavonoid found in several edible and medicinal plants. It is recognized for its biological activities such as antioxidant, anti-inflammatory, neuroprotective, and antitumor effects. However, the limited water solubility of LUT leads to poor absorption after oral administration. Nanoencapsulation may improve the solubility of LUT. Nanoemulsions (NE) were selected for the encapsulation of LUT due to their biodegradability, stability, and ability to control drug release. In this work, chitosan (Ch)-based NE was developed to encapsulate luteolin (NECh-LUT). A 23 factorial design was built to obtain a formulation with optimized amounts of oil, water, and surfactants. NECh-LUT showed a mean diameter of 67.5 nm, polydispersity index 0.174, zeta potential of +12.8 mV, and encapsulation efficiency of 85.49%. Transmission electron microscopy revealed spherical shape and rheological analysis verified the Newtonian behavior of NECh-LUT. SAXS technique confirmed the bimodal characteristic of NECh-LUT, while stability analysis confirmed NECh-LUT stability when stored at room temperature for up to 30 days. Finally, in vitro release studies showed LUT controlled release up to 72 h, indicating the promising potential of NECh-LUT to be used as novel therapeutic option to treat several disorders.

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Helminth-induced eosinophils accumulate around the parasite at the site of infection, or in parasite-damaged tissues well after the helminth has left the site. The role of helminth-elicited eosinophils in mediating parasite control is complex. While they may contribute to direct parasite-killing and tissue repair, their involvement in long-term immunopathogenesis is a concern. In allergic Siglec-FhiCD101hi, eosinophils are associated with pathology. Research has not shown if equivalent subpopulations of eosinophils are a feature of helminth infection. In this study, we demonstrate that lung migration of rodent hookworm Nippostrongylus brasiliensis (Nb) results in a long-term expansion of distinct Siglec-FhiCD101hi eosinophil subpopulations. Nb-elevated eosinophil populations in the bone marrow and circulation did not present this phenotype. Siglec-FhiCD101hi lung eosinophils exhibited an activated morphology including nuclei hyper-segmentation and cytoplasm degranulation. Recruitment of ST2+ ILC2s and not CD4+ T cells to the lungs was associated with the expansion of Siglec-FhiCD101hi eosinophils. This data identifies a morphologically distinct and persistent subset of Siglec-FhiCD101hi lung eosinophils induced following Nb infection. These eosinophils may contribute to long-term pathology following helminth infection.

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Neutropenic fever (NF) is an oncologic emergency for which expert consensus recommends that anti-pseudomonas antibiotics be administered within 60 minutes of detection. This study investigated whether delays in time to antibiotics (TTA) impacted overall survival (OS) for patients with hematological malignancies who developed inpatient NF via a retrospective cohort study of 187 de novo NF cases categorized by TTA (<1, 1-2, 2-3, 3-4 and >4 hours). OS at 180 days post-NF episode was compared using Kaplan-Meier estimates and multivariable Cox proportional hazards model. TTA did not significantly affect OS (P = 0.420). Patients with Charleston Comorbidity Indexes ≥3, a measure of overall health, had higher hazard (hazard ratio [HR] = 2.728, 95% confidence interval, 1.265-5.882, P = 0.010). TTA delays in the hospital may not be long enough to cause significant patient harm. Larger studies may be needed to detect small, but significant mortality differences.

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PURPOSE: There are no universal guidelines for blood product transfusions in patients with hematologic malignancies (HMs). Excess utilization of platelet and RBC transfusion in patients with HM increases the cost of care and likelihood of adverse events. We aim to decrease the total number of transfused units and multiunit orders of platelets and RBCs in the HM clinic by 25% from March 2020 to December 2020. METHODS: A multidisciplinary, interprofessional team was formed. Baseline rates of blood product utilization were determined using Qlik Analytic software. Strategies to improve utilization were developed, and three interventions were initiated. Data were collected on monthly intervals. Data for total number of platelet and RBC units ordered, total multiunit orders, average number of units ordered per encounter, and pretransfusion hemoglobin thresholds were collected from May 2019 to December 2020. RESULTS: Through our Plan-Do-Study-Act cycles from March 2020 to December 2020, the total number of platelet transfusion orders per month decreased from 164 to 98, multiunit platelet orders decreased from 63 to 2, and the average number of platelet transfusions per encounter decreased from 1.62 to 1.03. The total number of RBC transfusion orders decreased from 172 to 141, multiunit RBC orders decreased from 25 to 16, and the average number of RBC transfusions per encounter decreased from 1.21 to 1.18. CONCLUSION: Implementation of our multidisciplinary interventions led to more appropriate use of blood products in the outpatient setting. Ongoing efforts are underway to continue to improve utilization in the inpatient and outpatient setting.

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PURPOSE: The purpose of this study was to develop the Oncology Opportunity Cost Assessment Tool (OOCAT), a survey instrument to evaluate the opportunity costs patients experience when seeking medical oncology care. METHODS: Development of the OOCAT involved extensive patient engagement through both focus groups and interviews. First, the study team developed a list of opportunity cost concepts, which included patients' logistical and financial considerations related to seeking care. We conducted focus groups with patients to expand upon this list of concepts, and then developed a set of questions that incorporated all the concepts generated during the focus groups. To refine these questions, we next performed cognitive interviews with another set of patients to ensure content validity and clarity of instrument items, refining the OOCAT iteratively on the basis of feedback. RESULTS: We engaged 23 participants (17 patients and six caregivers) across four focus groups and 17 participants in cognitive interviews. Focus group participants generated 112 concepts, which resulted in an initial OOCAT with 16 questions. Cognitive interviews resulted in modification of 12 questions and addition of two questions (related to coordination of transportation and impact on home responsibilities). The final OOCAT consisted of 18 items examining time requirements for appointments, financial implications of traveling to appointments for the patient and the caregiver, and logistical and quality-of-life challenges associated with traveling for appointments. CONCLUSION: We developed the OOCAT, an instrument designed to evaluate patient-level opportunity costs of seeking medical oncology care. Further studies to validate the OOCAT are underway.

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PURPOSE: The COVID-19 pandemic necessitated a rapid expansion of telehealth use in oncology, a specialty in which prior utilization was low in part because of barriers perceived by providers. Understanding the changing perceptions of medical oncology providers during the pandemic is critical for continued expansion and improvement of telehealth in cancer care. This study was designed to identify medical oncology providers' perceptions of telehealth video visits as influenced by the COVID-19 pandemic. METHODS: We conducted semi-structured interviews with medical oncology providers from November 20, 2020, to January 27, 2021, at the Sidney Kimmel Cancer Center at Thomas Jefferson University, a National Cancer Institute-designated cancer center in an urban, academic health system in Philadelphia, PA. We assessed provider perceptions of the impact of the COVID-19 pandemic on (1) provider-level comfort and willingness for telehealth, (2) provider-perceived patient comfort and willingness to engage in telehealth, and (3) continued barriers to successful telehealth use. RESULTS: Volunteer and convenience sampling resulted in the participation of 25 medical oncology providers, including 18 physicians and seven advanced practice providers, in semi-structured interviews. Of the 25 participants, 13 (52%) were female and 19 (76%) were White, with an average age of 48.5 years (standard deviation = 12.6). Respondents largely stated an increased comfort level and willingness for use of video visits. In addition, respondents perceived a positive change in patient comfort and willingness, mostly driven by convenience, accessibility, and reduced risk of COVID-19 exposure. However, several reported technologic issues and limited physical examination capability as remaining barriers to telehealth adoption. CONCLUSION: The rapid adoption of telehealth necessitated by the COVID-19 pandemic has increased provider-level and provider-perceived patient comfort and willingness to engage in video visits for cancer care. As both providers and patients increasingly accept telehealth across many use cases, future work should focus on further addressing technology and physical examination barriers and ensuring continued reimbursement for telehealth as a routine part of covered care.

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PURPOSE: Telehealth in medical oncology has expanded secondary to the COVID-19 pandemic. However, quantitative research on medical oncology telehealth use shows conflicting results on patient satisfaction, whereas qualitative data are sparse. Our qualitative study aimed to identify the factors influencing patient acceptability of video visits for medical oncology care before and at the onset of the expansion of telehealth because of the COVID-19 pandemic. METHODS: Semi-structured interviews were conducted between November 2019 and April 2020 with 20 patients who participated in a telehealth visit with a medical oncology provider at Thomas Jefferson University. RESULTS: Of the 20 participants, 13 (65%) were female and 15 (75%) were White, with a mean (standard deviation) age of 60.5 years (11.8). Patients identified convenience, anxiety, COVID-19, and provider preference as positively influencing the acceptability of video visits; however, some patients noted limitations in provider connection, physical examinations, and visit length as disadvantages. Regarding receipt of serious or bad news, some preferred video visits for privacy, immediacy of results, news processing, and family comfort. Others preferred in-person encounters for provider support and the ability to receive written information and in-person referrals. CONCLUSION: Patient-perceived factors influencing general acceptability, appropriateness of serious and bad news delivery, and future uses of telehealth were unique to each individual, but shared common themes. Understanding each patient's perspective of telehealth acceptability and tailoring use to their preferences is critical for continued utilization. Further research is needed to understand and address reasons for lack of telehealth uptake among certain patients.

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PURPOSE: Acute care utilization (ACU), including emergency department (ED) visits or hospital admissions, is common in patients with cancer and may be preventable. The Center for Medicare & Medicaid Services recently implemented OP-35, a measure in the Hospital Outpatient Quality Reporting Program focused on ED visits and inpatient admissions for 10 potentially preventable conditions that arise within 30 days of chemotherapy. This new measure exemplifies a growing focus on preventing unnecessary ACU. However, identifying patients at high risk of ACU remains a challenge. We developed a real-time clinical prediction model using a discrete point allocation system to assess risk for ACU in patients with active cancer. METHODS: We performed a retrospective cohort analysis of patients with active cancer from a large urban academic medical center. The primary outcome, ACU, was evaluated using a multivariate logistic regression model with backward variable selection. We used estimates from the multivariate logistic model to construct a risk index using a discrete point allocation system. RESULTS: Eight thousand two hundred forty-six patients were included in the analysis. ED utilization in the last 90 days, history of chronic obstructive pulmonary disease, congestive heart failure or renal failure, and low hemoglobin and low neutrophil count significantly increased risk for ACU. The model produced an overall C-statistic of 0.726. Patients defined as high risk (achieving a score of 2 or higher on the risk index) represented 10% of total patients and 46% of ACU. CONCLUSION: We developed an oncology acute care risk prediction model using a risk index-based scoring system, the REDUCE (Reducing ED Utilization in the Cancer Experience) score. Further efforts to evaluate the effectiveness of our model in predicting ACU are ongoing.

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PURPOSE: High-dose methotrexate (HD-MTX) is commonly used for the treatment of osteosarcoma or for CNS involvement in lymphoproliferative neoplasms. It is often given in the inpatient setting because of monitoring requirements after administration. We conducted a process improvement initiative to change our institutional discharge criteria for HD-MTX from 0.05 µmol/L to ≤ 0.1 µmol/L to reduce cost and length of stay (LOS) for this patient population. METHODS: After an assessment of drivers of LOS among patients receiving HD-MTX, we identified discharge criteria as an actionable factor. We developed a workflow to discharge patients with 3 days of oral leucovorin and sodium bicarbonate when the methotrexate level reached ≤ 0.1 µmol/L. Patient demographics, chemotherapy regimen, cycle, dose, and LOS data were collected for a 7-month period before and a 4-month period after the intervention. Cost savings were estimated on the basis of the daily cost of a hospital bed at the institution. RESULTS: Mean LOS for the pre-intervention and postintervention group was 4.84 days (n = 49) and 3.67 days (n = 42), respectively, resulting in a 24.4% reduction in LOS, with a mean ratio of 0.756 (95% CI, 0.615 to 0.927; P = .007). Reduced LOS resulted in a decrease in cost of $1,828.73 per admission, with a 4-month savings of $76, 806.56 and projected annualized savings of $230,419.67. No patient experienced complications because of the change in discharge criteria. CONCLUSION: Liberalizing discharge criteria for HD-MTX was feasible and safe and reduced cost. Additional efforts to reduce LOS for elective chemotherapy admissions or to safely transition some of these complex regimens to the home setting are currently underway at our institution.

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In tropical regions, fires propagate readily in grasslands but typically consume only edges of forest patches. Thus, forest patches grow due to tree propagation and shrink by fires in surrounding grasslands. The interplay between these competing edge effects is unknown, but critical in determining the shape and stability of individual forest patches, as well the landscape-level spatial distribution and stability of forests. We analyze high-resolution remote-sensing data from protected Brazilian Cerrado areas and find that forest shapes obey a robust perimeter-area scaling relation across climatic zones. We explain this scaling by introducing a heterogeneous fire propagation model of tropical forest-grassland ecotones. Deviations from this perimeter-area relation determine the stability of individual forest patches. At a larger scale, our model predicts that the relative rates of tree growth due to propagative expansion and long-distance seed dispersal determine whether collapse of regional-scale tree cover is continuous or discontinuous as fire frequency changes.

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Several microbial components, such as bacterial DNA and flagellin, have been used as experimental vaccine adjuvants because of their inherent capacity to efficiently activate innate immune responses. Likewise, our previous work has shown that the major Salmonella Typhi (S. Typhi) outer membrane proteins OmpC and OmpF (porins) are highly immunogenic protective antigens that efficiently stimulate innate and adaptive immune responses in the absence of exogenous adjuvants. Moreover, S. Typhi porins induce the expression of costimulatory molecules on antigen-presenting cells through toll-like receptor canonical signaling pathways. However, the potential of major S. Typhi porins to be used as vaccine adjuvants remains unknown. Here, we evaluated the adjuvant properties of S. Typhi porins against a range of experimental and clinically relevant antigens. Co-immunization of S. Typhi porins with ovalbumin (OVA), an otherwise poorly immunogenic antigen, enhanced anti-OVA IgG titers, antibody class switching, and affinity maturation. This adjuvant effect was dependent on CD4+ T-cell cooperation and was associated with an increase in IFN-γ, IL-17A, and IL-2 production by OVA-specific CD4+ T cells. Furthermore, co-immunization of S. Typhi porins with an inactivated H1N1 2009 pandemic influenza virus experimental vaccine elicited higher hemagglutinating anti-influenza IgG titers, antibody class switching, and affinity maturation. Unexpectedly, co-administration of S. Typhi porins with purified, unconjugated Vi capsular polysaccharide vaccine (Vi CPS)-a T-independent antigen-induced higher IgG antibody titers and class switching. Together, our results suggest that S. Typhi porins OmpC and OmpF are versatile vaccine adjuvants, which could be used to enhance T-cell immune responses toward a Th1/Th17 profile, while improving antibody responses to otherwise poorly immunogenic T-dependent and T-independent antigens.

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Tropical savannas are hypothesized to be hot spots of nitrogen-fixer diversity and activity because of the high disturbance and low nitrogen characteristic of savanna landscapes. Here we compare the abundances of nitrogen-fixing and non-fixing trees in both tropical savannas and tropical forests under climatically equivalent conditions, using plant inventory studies across 566 plots in South America and Africa. A single factor, aridity, explained 19-54% of the variance in fixer abundance, and unexpectedly was more important than fire frequency, biome, and continent. Nitrogen fixers were more abundant in arid environments; as a result, African savannas, which tend to be drier, were richer in nitrogen fixers than South American savannas. Fixer abundance converged on similar levels in forests in both continents. We conclude that climate plays a greater role than fire in determining the distribution of nitrogen fixers across tropical savanna and forest biomes.

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In the present work, we report, for the first time, on the purification of the Salmonella Typhimurium OmpD porin. We assessed the integrity and purity of the protein and evaluated the immunogenicity of the protein and its ability to induce antibody without exogenous adjuvant. We observed that 10 µg OmpD induced high antibody levels of IgM and IgG, which were maintained for more than 260 days after immunization. Immunization with OmpD induced multiple IgG antibody isotypes including IgG1, IgG2a, IgG2b, and IgG3 subclasses. Furthermore, these antibodies were able to recognize and bind to the bacterial surface. Our results demonstrate the high immunogenicity of S. Typhimurium OmpD porin, which induces long-lasting antibodies which may be and important target of the immune response against Salmonella infection. In conclusion, we propose the OmpD porin could be used within novel subunit vaccine formulations that do not need additional adjuvant and that confer long lasting humoral immunity against Salmonella infections.

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Nutrients have been hypothesized to influence the distribution of the savanna biome through two possible mechanisms. Low nutrient availability may restrict growth rates of trees, thereby allowing for intermittent fires to maintain low tree cover; alternatively, nutrient deficiency may even place an absolute constraint on the ability of forests to form, independent of fire. However, we have little understanding of the scales at which nutrient limitation operates, what nutrients are limiting, and the mechanisms that influence how nutrient limitation regulates savanna-forest transitions. Here, I review literature, synthesize existing data, and present a simple calculation of nutrient demand to evaluate how nutrient limitation may regulate the distribution of the savanna biome. The literature primarily supports the hypothesis that nutrients may interact dynamically with fire to restrict the transition of savanna into forest. A compilation of indirect metrics of nutrient limitation suggest that nitrogen and phosphorus are both in short supply and may limit plants. Nutrient demand calculations provided a number of insights. First, trees required high rates of nitrogen and phosphorus supply relative to empirically determined inputs. Second, nutrient demand increased as landscapes approached the transition point between savanna and forest. Third, the potential for fire-driven nutrient losses remained high throughout transitions, which may exaggerate limitation and could be a key feedback stabilizing the savanna biome. Fourth, nutrient limitation varied between functional groups, with fast-growing forest species having substantially greater nutrient demand and a higher susceptibility to fire-driven nutrient losses. Finally, African savanna trees required substantially larger amounts of nutrients supplied at greater rates, although this varied across plant functional groups. In summary, the ability of nutrients to control transitions emerges at individual and landscape scales, and is regulated through different mechanisms based on spatial (differences in underlying geology), temporal (stage in biome transition) and biological (species traits and community composition) variability.

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Incentivizing carbon storage can be a win-win pathway to conserving biodiversity and mitigating climate change. In savannas, however, the situation is more complex. Promoting carbon storage through woody encroachment may reduce plant diversity of savanna endemics, even as the diversity of encroaching forest species increases. This trade-off has important implications for the management of biodiversity and carbon in savanna habitats, but has rarely been evaluated empirically. We quantified the nature of carbon-diversity relationships in the Brazilian Cerrado by analyzing how woody plant species richness changed with carbon storage in 206 sites across the 2.2 million km(2) region at two spatial scales. We show that total woody plant species diversity increases with carbon storage, as expected, but that the richness of endemic savanna woody plant species declines with carbon storage both at the local scale, as woody biomass accumulates within plots, and at the landscape scale, as forest replaces savanna. The sharpest trade-offs between carbon storage and savanna diversity occurred at the early stages of carbon accumulation at the local scale but the final stages of forest encroachment at the landscape scale. Furthermore, the loss of savanna species quickens in the final stages of forest encroachment, and beyond a point, savanna species losses outpace forest species gains with increasing carbon accumulation. Our results suggest that although woody encroachment in savanna ecosystems may provide substantial carbon benefits, it comes at the rapidly accruing cost of woody plant species adapted to the open savanna environment. Moreover, the dependence of carbon-diversity trade-offs on the amount of savanna area remaining requires land managers to carefully consider local conditions. Widespread woody encroachment in both Australian and African savannas and grasslands may present similar threats to biodiversity.

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Numerous predictions indicate rising CO2 will accelerate the expansion of forests into savannas. Although encroaching forests can sequester carbon over the short term, increased fires and drought-fire interactions could offset carbon gains, which may be amplified by the shift toward forest plant communities more susceptible to fire-driven dieback. We quantify how bark thickness determines the ability of individual tree species to tolerate fire and subsequently determine the fire sensitivity of ecosystem carbon across 180 plots in savannas and forests throughout the 2.2-million km(2) Cerrado region in Brazil. We find that not accounting for variation in bark thickness across tree species underestimated carbon losses in forests by ~50%, totaling 0.22 PgC across the Cerrado region. The lower bark thicknesses of plant species in forests decreased fire tolerance to such an extent that a third of carbon gains during forest encroachment may be at risk of dieback if burned. These results illustrate that consideration of trait-based differences in fire tolerance is critical for determining the climate-carbon-fire feedback in tropical savanna and forest biomes.

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BACKGROUND: The impact of exposure to multiple pathogens concurrently or consecutively on immune function is unclear. Here, immune responses induced by combinations of the bacterium Salmonella Typhimurium (STm) and the helminth Nippostrongylus brasiliensis (Nb), which causes a murine hookworm infection and an experimental porin protein vaccine against STm, were examined. METHODOLOGY/PRINCIPAL FINDINGS: Mice infected with both STm and Nb induced similar numbers of Th1 and Th2 lymphocytes compared with singly infected mice, as determined by flow cytometry, although lower levels of secreted Th2, but not Th1 cytokines were detected by ELISA after re-stimulation of splenocytes. Furthermore, the density of FoxP3+ T cells in the T zone of co-infected mice was lower compared to mice that only received Nb, but was greater than those that received STm. This reflected the intermediate levels of IL-10 detected from splenocytes. Co-infection compromised clearance of both pathogens, with worms still detectable in mice weeks after they were cleared in the control group. Despite altered control of bacterial and helminth colonization in co-infected mice, robust extrafollicular Th1 and Th2-reflecting immunoglobulin-switching profiles were detected, with IgG2a, IgG1 and IgE plasma cells all detected in parallel. Whilst extrafollicular antibody responses were maintained in the first weeks after co-infection, the GC response was less than that in mice infected with Nb only. Nb infection resulted in some abrogation of the longer-term development of anti-STm IgG responses. This suggested that prior Nb infection may modulate the induction of protective antibody responses to vaccination. To assess this we immunized mice with porins, which confer protection in an antibody-dependent manner, before challenging with STm. Mice that had resolved a Nb infection prior to immunization induced less anti-porin IgG and had compromised protection against infection. CONCLUSION: These findings demonstrate that co-infection can radically alter the development of protective immunity during natural infection and in response to immunization.

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