Naloxone-Prescribing Practices in a Freestanding Rehabilitation Hospital.

OBJECTIVE: The study aims to determine whether Physical Medicine & Rehabilitation physicians offer naloxone per the Centers for Disease Control and Prevention Guidelines to patients at the highest risk of complications from opioid treatment and whether there is a difference between inpatient and outpatient naloxone prescribing. DESIGN: A retrospective chart review on 389 adults (outpatient n = 166; inpatient n = 223) from May 4 to May 31, 2022, at an academic rehabilitation hospital. Prescribed medications and comorbidities were evaluated to determine whether Centers for Disease Control and Prevention criteria for offering naloxone were met and whether naloxone was offered. RESULTS: One hundred twenty-nine opioid prescriptions were written for 102 outpatients; 61 qualified for naloxone (morphine milliequivalent range = 10-1080, mean = 158.08). On inpatient, 68 patients received 86 opioid prescriptions; 35 qualified for naloxone (morphine milliequivalent range = 3.75-246, mean = 62.36). Overall, there was a significantly lower rate of opioid prescriptions for inpatients (30.49%) than outpatients (61.45%) ( P < 0.0001), a nonsignificant lower rate of inpatient (51.47%) than outpatient (59.80%) "at-risk" prescriptions ( P = 0.351), and a weakly significant lower rate of naloxone prescribing for inpatient (2.86%) than outpatient visits (8.20%) ( P < 0.0519). CONCLUSIONS: At this rehabilitation hospital, there was a low rate of naloxone prescribing by inpatient and outpatient providers, with a higher rate occurring in the outpatient than inpatient setting. More research is needed to understand this prescribing trend to determine potential interventions.

Ultrasound guidance versus landmark guidance for intrathecal baclofen pump refill: A randomized pilot study.

BACKGROUND: Refilling difficult-to-access intrathecal baclofen (ITB) pumps by a trainee can result in longer procedures, more needle punctures, and more frequent attending interventions. Though ultrasound guidance can be used, there has not been an investigation into the impact of ultrasound guidance on refill outcomes. OBJECTIVE: To determine the feasibility of ultrasound guidance during difficult ITB refills to improve the experience of patients and providers. DESIGN: Nonblinded, randomized controlled trial with crossover element. SETTING: Outpatient clinic at a tertiary academic rehabilitation hospital. PARTICIPANTS: Patients ≥18 years old with historically difficult refills who were scheduled for repeat refills. "Difficult" was defined as body mass index > 30.0, a deep/tilted pump, previously requiring >1 skin puncture, or previously needing special positioning to access. INTERVENTIONS: Consented participants were randomized into a template-guided group (control) or an ultrasound-guided group (experimental) using a coin flip. Patients were crossed over if (1) a second refill occurred during the study period or (2) the randomized technique failed. MAIN OUTCOME MEASURES: The primary measure was time spent with needle under skin (seconds). Number of needle punctures and needle passes, frequency of attending intervention, pain during and after the procedure, patient satisfaction, and practitioner perceived difficulty were investigated. RESULTS: Seventeen patients underwent 21 refills (12 template guided and 9 ultrasound guided). No patients experienced adverse events. Although without statistically significant difference, the average time in the experimental group was shorter than the control (175 seconds vs 401 seconds), there were fewer episodes of multiple needle punctures (0 vs 2), multiple needle passes (2 vs 5), and attending interventions (0 vs 3) in the experimental group. No significant/clinical difference was found in pain during procedure, pain after procedure, patient satisfaction, or practitioner subjective difficulty. CONCLUSIONS: This pilot study demonstrates that ultrasound-guided ITB refills may reduce time spent with the needle in the skin, number of needle punctures, number of needle passes, and frequency of attending intervention during trainee refilling of pumps that are difficult to access.

Creating and confirming observable professional activities (OPAs): A brief report on the practical approach for OPA design for resident education.

CONTEXT: The transition of graduate medical education to competency-based education systems has resulted in exploration of the efficacy of Entrustable Professional Activities (EPAs) and related Observable Practice Activities (OPAs) as evaluation tools. EPAs were introduced to PM&R in 2017, but no OPAs have been reported for a non-procedurally based EPA. The primary aims of this study were to create and form consensus on OPAs for the Spinal Cord Injury EPA. METHODS: A Modified Delphi panel of seven experts in the field was utilized to gain consensus on ten PM&R OPAs for the Spinal Cord Injury EPA. RESULTS: After the first round of evaluations, most OPAs were evaluated by experts as requiring modifications (30/70 votes to keep, 34/70 votes to modify) with a majority of comments focusing on the specific content of the OPAs. Edits were made, and after the second round, the OPAs were evaluated and determined to be kept (62/70 votes to keep, 6/70 votes to modify) with most edits being about semantics of the OPAs. Ultimately, there was significant difference in all three categories between round 1 and round 2 (P < 0.0001) and 10 OPAs were finalized for use. CONCLUSIONS: This study created 10 OPAs that can potentially help provide targeted feedback to residents on their competency in caring for patients with spinal cord injury. With regular usage, OPAs are designed to provide residents with insight into how they are progressing towards independent practice. In the future, studies should aim to assess the feasibility and utility of implementing the newly developed OPAs.

Multi-Omic Profiles in Infants at Risk for Food Reactions.

Food reactions (FR) are multifactorial and impacted by medical, demographic, environmental, and immunologic factors. We hypothesized that multi-omic analyses of host-microbial factors in saliva would enhance our understanding of FR development. This longitudinal cohort study included 164 infants followed from birth through two years. The infants were identified as FR (n = 34) or non-FR (n = 130) using the Infant Feeding Practice II survey and medical record confirmation. Saliva was collected at six months for the multi-omic assessment of cytokines, mRNAs, microRNAs, and the microbiome/virome. The levels of one miRNA (miR-203b-3p, adj. p = 0.043, V = 2913) and one viral phage (Proteus virus PM135, adj. p = 0.027, V = 2955) were lower among infants that developed FRs. The levels of one bacterial phylum (Cyanobacteria, adj. p = 0.048, V = 1515) were higher among infants that developed FR. Logistical regression models revealed that the addition of multi-omic features (miR-203b-3p, Cyanobacteria, and Proteus virus PM135) improved predictiveness for future FRs in infants (p = 0.005, X2 = 12.9), predicting FRs with 72% accuracy (AUC = 0.81, sensitivity = 72%, specificity = 72%). The multi-omic analysis of saliva may enhance the accurate identification of infants at risk of FRs and provide insights into the host/microbiome interactions that predispose certain infants to FRs.

Phylogenetic Analysis and Protein Modelling of Isoflavonoid Synthase Highlights Key Catalytic Sites towards Realising New Bioengineering Endeavours.

Isoflavonoid synthase (IFS) is a critical enzyme for the biosynthesis of over 2400 isoflavonoids. Isoflavonoids are an important class of plant secondary metabolites that have a range of pharmaceutical and nutraceutical properties. With growing interest in isoflavonoids from both research and industrial perspectives, efforts are being forwarded to enhance isoflavonoid production in-planta and ex-planta; therefore, in-silico analysis and characterisation of available IFS protein sequences are needed. The present study is the first-ever attempt toward phylogenetic analysis and protein modelling of available IFS protein sequences. Phylogenetic analysis has shown that IFS amino acid sequences have 86.4% pairwise identity and 26.5% identical sites, and the sequences were grouped into six different clades. The presence of a ß-hairpin and extra loop at catalytic sites of Trifolium pratense, Beta vulgaris and Medicago truncatula, respectively, compared with Glycyrrhiza echinata are critical structural differences that may affect catalytic function. Protein docking highlighted the preference of selected IFS for liquiritigenin compared with naringenin and has listed T. pratense as the most efficient candidate for heterologous biosynthesis of isoflavonoids. The in-silico characterisation of IFS represented in this study is vital in realising the new bioengineering endeavours and will help in the characterisation and selection of IFS candidate enzymes for heterologous biosynthesis of isoflavonoids.

Targeting Cross-Presentation as a Route to Improve the Efficiency of Peptide-Based Cancer Vaccines.

Cross-presenting dendritic cells (DC) offer an attractive target for vaccination due to their unique ability to process exogenous antigens for presentation on MHC class I molecules. Recent reports have established that these DC express unique surface receptors and play a critical role in the initiation of anti-tumor immunity, opening the way for the development of vaccination strategies specifically targeting these cells. This study investigated whether targeting cross-presenting DC by two complementary mechanisms could improve vaccine effectiveness, in both a viral setting and in a murine melanoma model. Our novel vaccine construct contained the XCL1 ligand, to target uptake to XCR1+ cross-presenting DC, and a cell penetrating peptide (CPP) with endosomal escape properties, to enhance antigen delivery into the cross-presentation pathway. Using a prime-boost regimen, we demonstrated robust expansion of antigen-specific T cells following vaccination with our CPP-linked peptide vaccine and protective immunity against HSV-1 skin infection, where vaccine epitopes were natively expressed by the virus. Additionally, our novel vaccination strategy slowed tumor outgrowth in a B16 murine melanoma model, compared to adjuvant only controls, suggesting antigen-specific anti-tumor immunity was generated following vaccination. These findings suggest that novel strategies to target the antigen cross-presentation pathway in DC may be beneficial for the generation of anti-tumor immunity.

Opioid stewardship training during the transition to residency to prepare medical students to recognize and treat opioid use disorder.

Background: With a drastic shortage of addiction medicine specialists-and an ever-growing number of patients with opioid use disorder (OUD)-there is a dire need for more clinicians to feel confident in prevention and management of OUD and obtain a DEA-X waiver to prescribe medications to treat OUD. Here we determine if it is feasible to certify 4th year medical students with DEA-X waiver training as a component of the PROUD (Prevent and Reduce Opioid Use Disorder) curriculum, and if PROUD enhanced preparedness for medical students to manage OUD as interns. Methods: We implemented a sequential mixed-methods IRB approved study to assess feasibility (completing all required components of DEA-X waiver training) and impact of PROUD (measured by knowledge growth, enhancement for residency, and utilization of training during internship). Students completed 11 hours of required OUD training. Quantitative data included pre-/post- knowledge and curriculum satisfaction assessments as well as long-term impact with follow up survey as interns. Qualitative data was collected by survey and semi-structured focus groups. Results: All 120 graduating medical students completed the required components of the curriculum. Knowledge improved on the Provider Clinical Support Services (12.9-17.3, p < 0.0001) and Brief Opioid Overdose Knowledge assessments (10.15-10.81, p < 0.0001). Course satisfaction was high: 90% recommended online modules; 85% recommended training overall. Six qualitative themes emerged: (1) curriculum content was practical, (2) online modules allowed flexibility, (3) in-person seminars ensured authenticity, (4) timing at the transition to residency was optimal, (5) curriculum enhanced awareness and confidence, and (6) training was applicable to future careers. At 3 months, 60% reported using their training during internship; 64% felt more prepared to treat OUD than peers. Conclusions: PROUD trained 4th year medical students in opioid stewardship. As interns, students felt ready to serve as change agents to prevent, diagnose, and treat OUD.

Recent Advances in Heterologous Synthesis Paving Way for Future Green-Modular Bioindustries: A Review With Special Reference to Isoflavonoids.

Isoflavonoids are well-known plant secondary metabolites that have gained importance in recent time due to their multiple nutraceutical and pharmaceutical applications. In plants, isoflavonoids play a role in plant defense and can confer the host plant a competitive advantage to survive and flourish under environmental challenges. In animals, isoflavonoids have been found to interact with multiple signaling pathways and have demonstrated estrogenic, antioxidant and anti-oncologic activities in vivo. The activity of isoflavonoids in the estrogen pathways is such that the class has also been collectively called phytoestrogens. Over 2,400 isoflavonoids, predominantly from legumes, have been identified so far. The biosynthetic pathways of several key isoflavonoids have been established, and the genes and regulatory components involved in the biosynthesis have been characterized. The biosynthesis and accumulation of isoflavonoids in plants are regulated by multiple complex environmental and genetic factors and interactions. Due to this complexity of secondary metabolism regulation, the export and engineering of isoflavonoid biosynthetic pathways into non-endogenous plants are difficult, and instead, the microorganisms Saccharomyces cerevisiae and Escherichia coli have been adapted and engineered for heterologous isoflavonoid synthesis. However, the current ex-planta production approaches have been limited due to slow enzyme kinetics and traditionally laborious genetic engineering methods and require further optimization and development to address the required titers, reaction rates and yield for commercial application. With recent progress in metabolic engineering and the availability of advanced synthetic biology tools, it is envisaged that highly efficient heterologous hosts will soon be engineered to fulfill the growing market demand.

Synthetic Biology towards Improved Flavonoid Pharmacokinetics.

Flavonoids are a structurally diverse class of natural products that have been found to have a range of beneficial activities in humans. However, the clinical utilisation of these molecules has been limited due to their low solubility, chemical stability, bioavailability and extensive intestinal metabolism in vivo. Recently, the view has been formed that site-specific modification of flavonoids by methylation and/or glycosylation, processes that occur in plants endogenously, can be used to improve and adapt their biophysical and pharmacokinetic properties. The traditional source of flavonoids and their modified forms is from plants and is limited due to the low amounts present in biomass, intrinsic to the nature of secondary metabolite biosynthesis. Access to greater amounts of flavonoids, and understanding of the impact of modifications, requires a rethink in terms of production, more specifically towards the adoption of plant biosynthetic pathways into ex planta synthesis approaches. Advances in synthetic biology and metabolic engineering, aided by protein engineering and machine learning methods, offer attractive and exciting avenues for ex planta flavonoid synthesis. This review seeks to explore the applications of synthetic biology towards the ex planta biosynthesis of flavonoids, and how the natural plant methylation and glycosylation pathways can be harnessed to produce modified flavonoids with more favourable biophysical and pharmacokinetic properties for clinical use. It is envisaged that the development of viable alternative production systems for the synthesis of flavonoids and their methylated and glycosylated forms will help facilitate their greater clinical application.

Corticosteroids: Review of the History, the Effectiveness, and Adverse Effects in the Treatment of Joint Pain.

BACKGROUND: Corticosteroids have been used for the past 70 years in the treatment of various musculoskeletal conditions. This includes its use for joint pain such as rheumatoid arthritis and osteoarthritis. OBJECTIVES: A narrative review of the literature from its initial discovery to the present day to summarize the research of corticosteroids for joint pain to determine the safety and effectiveness of this commonly used and prescribed medication. METHODS: A review of the literature was performed regarding the effectiveness and side effects of corticosteroids for joint and osteoarthritis conditions. RESULTS: The current evidence would suggest that the use of corticosteroids provides moderate short-term benefit for reducing pain and improving functioning. These benefits generally last several weeks without long-term effectiveness. In addition to its limited short-term effectiveness, there are multiple potential adverse effects including toxicity to articular cartilage and numerous systemic side effects such as increases in blood glucose levels, a reduction in immune function, and an increased risk of infections. LIMITATIONS: English only articles were reviewed. No attempt was made to perform a formal statistical or meta-analysis. CONCLUSIONS: The current evidence would suggest that the use of corticosteroids provides moderate evidence for short-term pain reduction and improvement in function. There are multiple potential adverse effects, such as toxic damage to articular cartilage, as well as numerous systemic side effects, including a reduction in immune function and an increased risk of infection, of which physicians need to be aware.

Hydrogen escape from Mars is driven by seasonal and dust storm transport of water.

Mars has lost most of its once-abundant water to space, leaving the planet cold and dry. In standard models, molecular hydrogen produced from water in the lower atmosphere diffuses into the upper atmosphere where it is dissociated, producing atomic hydrogen, which is lost. Using observations from the Neutral Gas and Ion Mass Spectrometer on the Mars Atmosphere and Volatile Evolution spacecraft, we demonstrate that water is instead transported directly to the upper atmosphere, then dissociated by ions to produce atomic hydrogen. The water abundance in the upper atmosphere varied seasonally, peaking in southern summer, and surged during dust storms, including the 2018 global dust storm. We calculate that this transport of water dominates the present-day loss of atomic hydrogen to space and influenced the evolution of Mars' climate.

Diverse Anti-Tumor Immune Potential Driven by Individual IFNα Subtypes.

Immunotherapies harnessing T cell immunity have shown remarkable clinical success for the management of cancer. However, only a proportion of patients benefit from these treatments. The presence of type I interferon (IFN) within the tumor microenvironment is critical for driving effective tumor-specific T cell immunity. Individuals can produce 12 distinct subtypes of IFNα, which all signal through a common receptor. Despite reported differences in anti-viral potencies, the concept that distinct IFNα subtypes can improve anti-cancer treatments remains unclear. We tested whether expression of unique IFNα subtypes confined to the tumor microenvironment enhances tumor control. This was systematically evaluated by transplantation of B16 murine melanoma cells secreting five unique IFNα subtypes (B16_IFNα2; B16_IFNα4; B16_IFNα5; B16_IFNα6; B16_IFNα9) into a pre-clinical murine model. We show that IFNα2 and IFNα9 are the only subtypes capable of completely controlling tumor outgrowth, with this protection dependent on the presence of an adaptive immune response. We next determined whether these differences extended to other model systems and found that the adoptive transfer of tumor-specific CD8+ T cells engineered to secrete IFNα9 delays tumor growth significantly and improves survival, whereas no enhanced survival was observed using T cells secreting IFNα4. Overall, our data shows that the expression of distinct IFNα subtypes within the tumor microenvironment results in different anti-tumor activities, and differentially affects the efficacy of a cancer therapy targeting established disease.

Feasibility and Impact of a Student-Led, Semi-Structured, Near-Peer Student Guides Program on Navigating Through Medical School.

BACKGROUND: Mentorship is critical to developing health professionals. Near-peer mentorship pairs senior mentors with junior peers to help navigate academic, professional, and social aspects of training. METHODS: In this convergent parallel mixed methods study, we assessed the feasibility, usability, professional and social impact, and barriers to implementation of a 16-week semi-structured, near-peer, student guides program involving 39 first year medical students (MS1s) and 41 fourth year medical students (MS4s). Student enrollment was quantified, guide-guidee meetings tracked, and > 2 meetings defined as feasible. Meeting topics, impact on student advising, and barriers to sustainability were contextualized qualitatively. RESULTS: Twenty-two percent of all MS4s and 46% of MS1s enrolled in the program; 67% of guides facilitated the requisite two meetings with their group, which was less than our predetermined feasibility criteria of 75%. Most guide-guidee interactions occurred in person (91%), but text messages (82%) and video/mobile messaging apps (78%) were also used. Ninety-two percent of guidees recommended the program, and 85% were satisfied with guidance received. Barriers included meeting coordination, infrequent meetings, and informal meeting structure. CONCLUSIONS: While the program was infeasible by predefined frequency criteria, participant satisfaction was high and academic, professional, and social benefits of near-peers were reported. In response, programmatic revisions now incorporate centralized support for meetings, e-mentorship, and guide training.

Management of Athletes With G6PD Deficiency: Does Missing an Enzyme Mean Missing More Games?

CONTEXT: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is likely the most prevalent enzyme deficiency on the planet, with an estimated 4.9% of people, or approximately 330 million individuals, across the globe affected by the disease. In the United States, 4% to 7% of the population is likely affected, but each year our nation's major sport leagues become more international. It is important for medical professionals who treat athletes to understand how this genetic condition can affect the athletes we are working with, especially because exercise in itself results in oxidative stress. EVIDENCE ACQUISITION: PubMed was searched for relevant articles published from 1980 to 2018. The search terms G6PD, athletes, military, and sports were used. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 4. RESULTS: Though some case reports suggest a potential impact on athlete safety and performance, controlled studies demonstrate limited impact of exercise on oxidative stress in G6PD-deficient individuals. The care of athletes with G6PD deficiency does not drastically differ from the care of athletes without this condition. Most of the medications and supplements that are regularly given to athletes should not negatively affect their health. CONCLUSION: Although the care of athletes with G6PD deficiency is for the most part no different from the care of other athletes, there are certain situations (visiting areas where malaria is endemic) and medications for which it is important to recognize how your management should change. G6PD deficiency is not regularly screened for but could be considered if an athlete has known sickle cell disease or when traveling to areas where malaria is prevalent. Expanding our knowledge of G6PD deficiency will allow for better care of athletes.

Acquired resistance during adoptive cell therapy by transcriptional silencing of immunogenic antigens.

Immunotherapies such as adoptive cell therapy (ACT) are promising treatments for solid cancers. However, relapsing disease remains a problem and the molecular mechanisms underlying resistance are poorly defined. We postulated that the deregulated epigenetic landscape in cancer cells could underpin the acquisition of resistance to immunotherapy. To address this question, two preclinical models of ACT were employed to study transcriptional and epigenetic regulatory processes within ACT-treated cancer cells. In these models ACT consistently causes robust tumor regression, but resistance develops and tumors relapse. We identified down-regulated expression of immunogenic antigens at the mRNA level correlated with escape from immune control. To determine whether this down-regulation was under epigenetic control, we treated escaped tumor cells with DNA demethylating agents, azacytidine (AZA) and decitabine (DEC). AZA or DEC treatment restored antigen expression in a proportion of the tumor population. To explore the importance of other epigenetic modifications we isolated tumor cells refractory to DNA demethylation and screened clones against a panel of 19 different epigenetic modifying agents (EMAs). The library of EMAs included inhibitors of a range of chromosomal and transcription regulatory protein complexes, however, when tested as single agents none restored further antigen expression. These findings suggest that tumor cells employ multiple epigenetic and genetic mechanisms to evade immune control, and a combinatorial approach employing several EMAs targeting transcription and genome stability may be required to overcome tumor resistance to immunotherapy.

A platform for discovery of functional cell-penetrating peptides for efficient multi-cargo intracellular delivery.

Cell penetrating peptides (CPPs) offer great potential to deliver therapeutic molecules to previously inaccessible intracellular targets. However, many CPPs are inefficient and often leave their attached cargo stranded in the cell's endosome. We report a versatile platform for the isolation of peptides delivering a wide range of cargos into the cytoplasm of cells. We used this screening platform to identify multiple "Phylomer" CPPs, derived from bacterial and viral genomes. These peptides are amenable to conventional sequence optimization and engineering approaches for cell targeting and half-life extension. We demonstrate potent, functional delivery of protein, peptide, and nucleic acid analog cargos into cells using Phylomer CPPs. We validate in vivo activity in the cytoplasm, through successful transport of an oligonucleotide therapeutic fused to a Phylomer CPP in a disease model for Duchenne's muscular dystrophy. This report thus establishes a discovery platform for identifying novel, functional CPPs to expand the delivery landscape of druggable intracellular targets for biological therapeutics.

ß-Lactamase Tools for Establishing Cell Internalization and Cytosolic Delivery of Cell Penetrating Peptides.

The ability of cell penetrating peptides (CPPs) to deliver biologically relevant cargos into cells is becoming more important as targets in the intracellular space continue to be explored. We have developed two assays based on CPP-dependent, intracellular delivery of TEM-1 ß-lactamase enzyme, a functional biological molecule comparable in size to many protein therapeutics. The first assay focuses on the delivery of full-length ß-lactamase to evaluate the internalization potential of a CPP sequence. The second assay uses a split-protein system where one component of ß-lactamase is constitutively expressed in the cytoplasm of a stable cell line and the other component is delivered by a CPP. The delivery of a split ß-lactamase component evaluates the cytosolic delivery capacity of a CPP. We demonstrate that these assays are rapid, flexible and have potential for use with any cell type and CPP sequence. Both assays are validated using canonical and novel CPPs, with limits of detection from <500 nM to 1 µM. Together, the ß-lactamase assays provide compatible tools for functional characterization of CPP activity and the delivery of biological cargos into cells.

CD8+XCR1neg Dendritic Cells Express High Levels of Toll-Like Receptor 5 and a Unique Complement of Endocytic Receptors.

Conventional dendritic cells (cDC) resident in the lymphoid organs of mice have been classically divided into CD8+ and CD8neg subsets. It is well-established that CD8+ dendritic cells (DCs) and their migratory counterparts in the periphery comprise the cross-presenting cDC1 subset. In contrast, CD8neg DCs are grouped together in the heterogeneous cDC2 subset. CD8neg DCs are relatively poor cross-presenters and drive more prominent CD4+ T cell responses against exogenous antigens. The discovery of the X-C motif chemokine receptor 1 (XCR1) as a specific marker of cross-presenting DCs, has led to the identification of a divergent subset of CD8+ DCs that lacks the ability to cross-present. Here, we report that these poorly characterized CD8+XCR1neg DCs have a gene expression profile that is consistent with both plasmacytoid DCs (pDCs) and cDC2. Our data demonstrate that CD8+XCR1neg DCs possess a unique pattern of endocytic receptors and a restricted toll-like receptor (TLR) profile that is particularly enriched for TLR5, giving them a unique position within the DC immunosurveillance network.