Prehospital Testing and Surveillance for SARS-CoV-2: A Special Report from the Sacramento (California USA) Mobile Integrated Health Unit.

INTRODUCTION: Coronavirus disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has killed nearly 800,000 Americans since early 2020. The disease has disproportionately affected older Americans, men, persons of color, and those living in congregate living facilities. Sacramento County (California USA) has used a novel Mobile Integrated Health Unit (MIH) to test hundreds of patients who dwell in congregate living facilities, including skilled nursing facilities (SNF), residential care facilities (ie, assisted living facilities [ALF] and board and care facilities [BCF]), and inpatient psychiatric facilities (PSY), for SARS-CoV-2. METHODS: The MIH was authorized and rapidly created at the beginning of the COVID-19 pandemic as a joint venture between the Sacramento County Department of Public Health (SCDPH) and several fire-based Emergency Medical Services (EMS) agencies within the county to perform SARS-CoV-2 testing and surveillance in a prehospital setting at a number of congregate living facilities. All adult patients (≥18 years) who were tested for SARS-CoV-2 infection by the MIH from March 31, 2020 through April 30, 2020 and lived in congregate living facilities were included in this retrospective descriptive cohort. Demographic and laboratory data were collected to describe the cohort of patients tested by the MIH. RESULTS: During the study period, the MIH tested a total of 323 patients from 15 facilities in Sacramento County. The median age of patients tested was 66 years and the majority were female (72%). Overall, 72 patients (22%) tested positive for SARS-CoV-2 in congregate living settings, a higher rate of positivity than was measured across the county during the same time period. CONCLUSION: The MIH was a novel method of epidemic surveillance that succeeded in delivering effective and efficient testing to patients who reside in congregate living facilities and was able to accurately identify pockets of infection within otherwise low prevalence areas. Cooperative prehospital models are an effective model to deliver out-of-hospital testing and disease surveillance that may serve as a blueprint for community-based care delivery for a number of disease states and future epidemics or pandemics.

IgG Fc sialylation is regulated during the germinal center reaction following immunization with different adjuvants.

BACKGROUND: Effector functions of IgG Abs are regulated by their Fc N-glycosylation pattern. IgG Fc glycans that lack galactose and terminal sialic acid residues correlate with the severity of inflammatory (auto)immune disorders and have also been linked to protection against viral infection and discussed in the context of vaccine-induced protection. In contrast, sialylated IgG Abs have shown immunosuppressive effects. OBJECTIVE: We sought to investigate IgG glycosylation programming during the germinal center (GC) reaction following immunization of mice with a foreign protein antigen and different adjuvants. METHODS: Mice were analyzed for GC T-cell, B-cell, and plasma cell responses, as well as for antigen-specific serum IgG subclass titers and Fc glycosylation patterns. RESULTS: Different adjuvants induce distinct IgG+ GC B-cell responses with specific transcriptomes and expression levels of the α2,6-sialyltransferase responsible for IgG sialylation that correspond to distinct serum IgG Fc glycosylation patterns. Low IgG Fc sialylation programming in GC B cells was overall highly dependent on the Foxp3- follicular helper T (TFH) cell-inducing cytokine IL-6, here in particular induced by water-in-oil adjuvants and Mycobacterium tuberculosis. Furthermore, low IgG Fc sialylation programming was dependent on adjuvants that induced IL-27 receptor-dependent IFN-γ+ TFH1 cells, IL-6/IL-23-dependent IL-17A+ TFH17 cells, and high ratios of TFH cells to Foxp3+ follicular regulatory T cells. Here, the 2 latter were dependent on M tuberculosis and its cord factor. CONCLUSION: This study's findings regarding adjuvant-dependent GC responses and IgG glycosylation programming may aid in the development of novel vaccination strategies to induce IgG Abs with both high affinity and defined Fc glycosylation patterns in the GC.

Griffithsin Inhibits Nipah Virus Entry and Fusion and Can Protect Syrian Golden Hamsters From Lethal Nipah Virus Challenge.

Nipah virus (NiV) is a highly pathogenic zoonotic paramyxovirus that causes fatal encephalitis and respiratory disease in humans. There is currently no approved therapeutic for human use against NiV infection. Griffithsin (GRFT) is high-mannose oligosaccharide binding lectin that has shown in vivo broad-spectrum activity against viruses, including severe acute respiratory syndrome coronavirus, human immunodeficiency virus 1, hepatitis C virus, and Japanese encephalitis virus. In this study, we evaluated the in vitro antiviral activities of GRFT and its synthetic trimeric tandemer (3mG) against NiV and other viruses from 4 virus families. The 3mG had comparatively greater potency than GRFT against NiV due to its enhanced ability to block NiV glycoprotein-induced syncytia formation. Our initial in vivo prophylactic evaluation of an oxidation-resistant GRFT (Q-GRFT) showed significant protection against lethal NiV challenge in Syrian golden hamsters. Our results warrant further development of Q-GRFT and 3mG as potential NiV therapeutics.

Capacity Building for and Implementation of Policy, Systems, and Environmental Change: Results from a Survey of the National Comprehensive Cancer Control Program.

Policy, systems, and environmental (PSE) approaches are commonly used to improve population health. Cancer-related examples include providing data and education to stakeholders about policies that support healthy living, or health systems changes such as universal reminders about recommended cancer screening. The National Comprehensive Cancer Control Program (NCCCP) funds health departments to form cancer coalitions that develop and implement cancer plans. NCCCP initiated a demonstration program in 13 of 65 funded grantees to determine whether skilled, dedicated staffing and using a strategic process to examine data, form a workgroup, and develop an agenda would enhance their capacity to implement PSE approaches, recruit new partners, and provide data and education to stakeholders. The objective of this study was to compare demonstration program grantees to other NCCCP grantees on their ability to develop and implement PSE strategies, and the short-term results that were achieved. Program directors (PDs) from each NCCCP-funded jurisdiction completed web surveys at 2 time points during implementation to assess changes in their capacity for PSE approaches, identify implementation activities, and document short-term outcomes. Responses from demonstration program PDs and other PDs at both time points were compared in a descriptive analysis. Demonstration program grantees experienced greater increases in skills and capacity to address PSE approaches, engaged in necessary implementation activities more often, and achieved greater improvements in stakeholder and decision maker awareness and support for PSE strategies, compared to nonparticipating NCCCP grantees. These findings support continued implementation of PSE approaches for sustainable cancer prevention and control.

Prioritizing Population Approaches in Cancer Prevention and Control: Results of a Case Study Evaluation of Policy, Systems, and Environmental Change.

Development and implementation of policy, systems, and environmental (PSE) change is a commonly used public health approach to reduce disease burden. The Centers for Disease Control and Prevention's National Comprehensive Cancer Control Program conducted a demonstration with 13 programs to determine whether and to what extent dedicated resources would enhance the adoption of PSE strategies. This paper describes results of the qualitative portion of a longitudinal, mixed-methods evaluation of this demonstration. Case studies were conducted with a diverse subset of the 13 programs, and 106 in-depth interviews were completed with state/tribal program staff, community partners, and decision makers. Interviews addressed PSE change planning and capacity building, partnerships, local context, and how programs achieved PSE change. Dedicated PSE resources, including a policy analyst, helped increase PSE change capacity, intensify focus on PSE change overall, and accomplish specific PSE changes within individual jurisdictions. Stakeholders described PSE change as a gradual process requiring preparation and prioritization, strategic collaboration, and navigation of local context. Findings suggest that the demonstration program, including PSE-dedicated funds and a policy analyst, was successful in both increasing PSE change capacity and achieving PSE change itself. These results may be useful to other state, tribal, territorial, and public health organizations planning or implementing PSE change strategies.

Over-expressing the soluble gp130-Fc does not ameliorate methionine and choline deficient diet-induced non alcoholic steatohepatitis in mice.

Non-alcoholic steatohepatitis (NASH) is a liver disease with the potential to lead to cirrhosis and hepatocellular carcinoma. Interleukin-6 (IL-6) has been implicated in the pathogenesis of NASH, with the so-called IL-6 'trans-signaling' cascade being responsible for the pro-inflammatory actions of this cytokine. We aimed to block IL-6 'trans-signaling', using a transgenic mouse that overexpresses human soluble glycoprotein130 (sgp130Fc Tg mice) fed a commonly used dietary model of inducing NASH (methionine and choline deficient-diet; MCD diet) and hypothesized that markers of NASH would be ameliorated in such mice. Sgp130Fc Tg and littermate control mice were fed a MCD or control diet for 4 weeks. The MCD diet induced many hallmarks of NASH including hepatomegaly, steatosis, and liver inflammation. However, in contrast with other mouse models and, indeed, human NASH, the MCD diet model did not increase the mRNA or protein expression of IL-6. Not surprisingly, therefore, markers of MCD diet-induced NASH were unaffected by sgp130Fc transgenic expression. While the MCD diet model induces many pathophysiological markers of NASH, it does not induce increased IL-6 expression in the liver, a key hallmark of human NASH. We, therefore, caution the use of the MCD diet as a viable mouse model of NASH.

IL-6 Improves Energy and Glucose Homeostasis in Obesity via Enhanced Central IL-6 trans-Signaling.

Interleukin (IL)-6 engages similar signaling mechanisms to leptin. Here, we find that central application of IL-6 in mice suppresses feeding and improves glucose tolerance. In contrast to leptin, whose action is attenuated in obesity, the ability of IL-6 to suppress feeding is enhanced in obese mice. IL-6 suppresses feeding in the absence of neuronal IL-6-receptor (IL-6R) expression in hypothalamic or all forebrain neurons of mice. Conversely, obese mice exhibit increased soluble IL-6R levels in the cerebrospinal fluid. Blocking IL-6 trans-signaling in the CNS abrogates the ability of IL-6 to suppress feeding. Furthermore, gp130 expression is enhanced in the paraventricular nucleus of the hypothalamus (PVH) of obese mice, and deletion of gp130 in the PVH attenuates the beneficial central IL-6 effects on metabolism. Collectively, these experiments indicate that IL-6 trans-signaling is enhanced in the CNS of obese mice, allowing IL-6 to exert its beneficial metabolic effects even under conditions of leptin resistance.

Live virus vaccines based on a vesicular stomatitis virus (VSV) backbone: Standardized template with key considerations for a risk/benefit assessment.

The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) was formed to evaluate the safety of live, recombinant viral vaccines incorporating genes from heterologous viral and other microbial pathogens in their genome (so-called "chimeric virus vaccines"). Many such viral vector vaccines are now at various stages of clinical evaluation. Here, we introduce an attenuated form of recombinant vesicular stomatitis virus (rVSV) as a potential chimeric virus vaccine for HIV-1, with implications for use as a vaccine vector for other pathogens. The rVSV/HIV-1 vaccine vector was attenuated by combining two major genome modifications. These modifications acted synergistically to greatly enhance vector attenuation and the resulting rVSV vector demonstrated safety in sensitive mouse and non-human primate neurovirulence models. This vector expressing HIV-1 gag protein has completed evaluation in two Phase I clinical trials. In one trial the rVSV/HIV-1 vector was administered in a homologous two-dose regimen, and in a second trial with pDNA in a heterologous prime boost regimen. No serious adverse events were reported nor was vector detected in blood, urine or saliva post vaccination in either trial. Gag specific immune responses were induced in both trials with highest frequency T cell responses detected in the prime boost regimen. The rVSV/HIV-1 vector also demonstrated safety in an ongoing Phase I trial in HIV-1 positive participants. Additionally, clinical trial material has been produced with the rVSV vector expressing HIV-1 env, and Phase I clinical evaluation will initiate in the beginning of 2016. In this paper, we use a standardized template describing key characteristics of the novel rVSV vaccine vectors, in comparison to wild type VSV. The template facilitates scientific discourse among key stakeholders by increasing transparency and comparability of information. The Brighton Collaboration V3SWG template may also be useful as a guide to the evaluation of other recombinant viral vector vaccines.

Projections to achieve minimum surgical rate threshold: an observational study.

BACKGROUND: Recent work has indicated an increase in surgical services, especially in resource poor settings. However, the rate of growth is poorly understood and likely insufficient to meet public health needs. We previously identified a range of 4344 to 5028 operations per 100 000 population annually to be related to desirable health outcomes. From this and other evidence, the Lancet Commission on Global Surgery recommends a minimum rate of 5000 operations per 100 000 population. We evaluate rates of growth in surgery and estimate the time it will take to reach this minimum surgical rate threshold. METHODS: We aggregated 2004 and 2012 country-level surgical rate estimates into the 21 Global Burden of Disease (GBD) regions. We calculated mean rates of surgery proportional to population size and estimate rate of growth between these years. We then extrapolated the time it will take to reach a surgical rate of 5000 operations per 100 000 population based on linear rates of change. FINDINGS: All but two regions (central Europe and southern Latin America) experienced growth in their surgical rates during the past 8 years; the fastest growth occurred in regions with the lowest surgical rates. 14 regions representing 79% of the world's population (5·5 billion people) did not meet the recommended surgical rate threshold in 2012. If surgical capacity grows at current rates, seven regions (central sub-Saharan Africa, east Asia, eastern sub-Saharan Africa, north Africa and middle east, south Asia, southeast Asia, and western sub-Saharan Africa) will not meet the recommended surgical rate threshold by 2035; Eastern Sub-Saharan Africa will not reach this level until 2124. INTERPRETATION: The rates of growth in surgical service delivery are exceedingly variable, but the largest growth rates were noted in the poorest regions. Although this study does not address the quality of care, and rates of surgery are unlikely to change linearly, this exercise is useful to project how many years it could take regions to reach specific surgical rates. At current rates of growth, 4·9 billion people (70% of the world's population) will still be living in countries below the minimum recommended rate of surgery in 2035. A strategy for strengthening surgical capacity is essential if these targets are to be met as part of integrated health system development. FUNDING: None.

Comprehensive Cancer Control Partners' Use of and Attitudes About Evidence-Based Practices.

INTRODUCTION: National Comprehensive Cancer Control Program (NCCCP) awardees are encouraged to work with partners (eg, nonprofit organizations) to develop and implement plans to reduce the cancer burden in their jurisdictions using evidence-based practices (EBPs). However, the extent of EBP use among awardees and their partners is not well understood. METHODS: From March through July 2012, we conducted a web-based survey of program partners referred by NCCCP program directors who were involved in implementation of cancer control plans. RESULTS: Approximately 53% of referred partners (n = 83) completed surveys, 91.6% of whom represented organizations. Most partners reported involvement in helping to identify (80.5%), adapt (81.7%), implement (90.4%), and evaluate (81.9%) EBPs. The factors rated most frequently as very important when selecting EBPs were "consistent with our organization's mission" (89.2%) and "cost-effective" (81.9%). Although most respondents said that their organizations understood the importance of using EBPs (84.3%) and had adequate access to cancer registry data (74.7%), few reported having sufficient financial resources to develop new EBPs (7.9%). The most frequently mentioned benefit of using EBPs was that they are proven to work. Resource limitations and difficulty adapting EBPs for specific populations and settings were challenges. CONCLUSIONS: Our findings help indicate how NCCCP partners are involved in using EBPs and can guide ongoing efforts to encourage the use of EBPs for cancer control. The challenges of using EBPs that partners identified highlight the need to improve strategies to translate cancer prevention and control research into practice in real-world settings and for diverse populations.

Projections for Achieving the Lancet Commission Recommended Surgical Rate of 5000 Operations per 100,000 Population by Region-Specific Surgical Rate Estimates.

BACKGROUND: We previously identified a range of 4344-5028 annual operations per 100,000 people to be related to desirable health outcomes. From this and other evidence, the Lancet Commission on Global Surgery recommends a minimum rate of 5000 operations per 100,000 people. We evaluate rates of growth and estimate the time it will take to reach this minimum surgical rate threshold. METHODS: We aggregated country-level surgical rate estimates from 2004 to 2012 into the twenty-one Global Burden of Disease (GBD) regions. We calculated mean rates of surgery proportional to population size for each year and assessed the rate of growth over time. We then extrapolated the time it will take each region to reach a surgical rate of 5000 operations per 100,000 population based on linear rates of change. RESULTS: All but two regions experienced growth in their surgical rates during the past 8 years. Fourteen regions did not meet the recommended threshold in 2012. If surgical capacity continues to grow at current rates, seven regions will not meet the threshold by 2035. Eastern Sub-Saharan Africa will not reach the recommended threshold until 2124. CONCLUSION: The rates of growth in surgical service delivery are exceedingly variable. At current rates of surgical and population growth, 6.2 billion people (73% of the world's population) will be living in countries below the minimum recommended rate of surgical care in 2035. A strategy for strengthening surgical capacity is essential if these targets are to be met in a timely fashion as part of the integrated health system development.

Use of Evidence-Based Practices and Resources Among Comprehensive Cancer Control Programs.

CONTEXT: While efforts to promote use of evidence-based practices (EBPs) for cancer control have increased, questions remain whether this will result in widespread adoption of EBPs (eg, Guide to Community Preventive Services interventions) by comprehensive cancer control (CCC) programs. OBJECTIVE: To examine use of EBPs among CCC programs to develop cancer control plans and select interventions. DESIGN: Conducted Web-based surveys of and telephone interviews with CCC program staff between March and July 2012. SETTING: CCC programs funded by the Centers for Disease Control and Prevention's National Comprehensive Cancer Control Program (NCCCP). PARTICIPANTS: Sixty-one CCC program directors. MAIN OUTCOME MEASURES: 1) Use of and knowledge/attitudes about EBPs and related resources and 2) EBP-related technical assistance needs. RESULTS: Seventy-five percent of eligible program directors reported use of EBPs to a moderate or great extent to address program objectives. Benefits of using EBPS included their effectiveness has been proven, they are an efficient use of resources, and they lend credibility to an intervention. Challenges to using EBPs included resource limitations, lack of culturally appropriate interventions, and limited skills adapting EBPs for local use. Most respondents had heard of and used Web sites for The Guide to Community Preventive Services (95% and 91%, respectively) and Cancer Control P.L.A.N.E.T. (98% and 75%, respectively). Training needs included how to adapt an EBP and its materials for cultural appropriateness (state 78%, tribe 86%, territory 80%) and how to maintain the fidelity of an EBP (state 75%, tribe 86%, territory 60%). CONCLUSIONS: While awareness, knowledge, and use of EBPs and related resources are high, respondents identified numerous challenges and training needs. The findings from this study may be used to enhance technical assistance provided to NCCCP grantees related to selecting and implementing EBPs.

Folic acid handling by the human gut: implications for food fortification and supplementation.

BACKGROUND: Current thinking, which is based mainly on rodent studies, is that physiologic doses of folic acid (pterylmonoglutamic acid), such as dietary vitamin folates, are biotransformed in the intestinal mucosa and transferred to the portal vein as the natural circulating plasma folate, 5-methyltetrahydrofolic acid (5-MTHF) before entering the liver and the wider systemic blood supply. OBJECTIVE: We tested the assumption that, in humans, folic acid is biotransformed (reduced and methylated) to 5-MTHF in the intestinal mucosa. DESIGN: We conducted a crossover study in which we sampled portal and peripheral veins for labeled folate concentrations after oral ingestion with physiologic doses of stable-isotope-labeled folic acid or the reduced folate 5-formyltetrahydrofolic acid (5-FormylTHF) in 6 subjects with a transjugular intrahepatic porto systemic shunt (TIPSS) in situ. The TIPSS allowed blood samples to be taken from the portal vein. RESULTS: Fifteen minutes after a dose of folic acid, 80 ± 12% of labeled folate in the hepatic portal vein was unmodified folic acid. In contrast, after a dose of labeled 5-FormylTHF, only 4 ± 18% of labeled folate in the portal vein was unmodified 5-FormylTHF, and the rest had been converted to 5-MTHF after 15 min (postdose). CONCLUSIONS: The human gut appears to have a very efficient capacity to convert reduced dietary folates to 5-MTHF but limited ability to reduce folic acid. Therefore, large amounts of unmodified folic acid in the portal vein are probably attributable to an extremely limited mucosal cell dihydrofolate reductase (DHFR) capacity that is necessary to produce tetrahydrofolic acid before sequential methylation to 5-MTHF. This process would suggest that humans are reliant on the liver for folic acid reduction even though it has a low and highly variable DHFR activity. Therefore, chronic liver exposure to folic acid in humans may induce saturation, which would possibly explain reports of systemic circulation of unmetabolized folic acid.

Vitamin D as a clinical biomarker in multiple sclerosis.

INTRODUCTION: Vitamin D has attracted a lot of attention in relation to multiple sclerosis (MS) and many other disorders; however, the evidence for a major role(s) for vitamin D in MS is compelling and multifactorial involving results from epidemiology, immunology, genetics, biochemistry and translational medicine. AREAS COVERED: Multiple studies that illustrate that insufficient levels of vitamin D not only contribute to the risk of getting MS but may also worsen disease progression for MS patients are discussed. Genetic evidence also implicates vitamin D as being important in MS since individuals are at greater risk of getting MS if they harbor a mutation in a gene responsible for vitamin D synthesis (25-hydroxylase). Other modifiers of MS disease appear to interact with the vitamin D receptor. The Epstein-Barr virus (EBV) is a risk factor for MS and may in part worsen disease through the interactions between one of its gene products (EBNA-3) and the vitamin D receptor to attenuate vitamin D-regulated genes. Retrospective studies have shown that higher vitamin D levels are associated with a significant improvement of clinical and magnetic resonance imaging outcomes. Increasing clinical observations are also indicating adverse effects of low vitamin D in MS. EXPERT OPINION: Mounting evidence from epidemiology, genetic, retrospective clinical studies and emerging basic science studies support a strong rationale for how vitamin D could be an important modifier of MS disease. Well-designed clinical trials are now ongoing and will provide further insight on how vitamin D supplementation may impact MS.

Anatomical position of hyaluronic Acid gel following injection to the infraorbital hollows.

PURPOSE: To examine with histology the anatomical location of hyaluronic acid gel injected to the infraorbital hollows of cadaver specimens. METHODS: The authors dissected 5 fresh hemifacial cadaver specimens following preperiosteal injection of hyaluronic acid gel to the infraorbital hollows. Following tissue fixation, full-thickness soft tissue sections were obtained along the medial, central, and lateral lower eyelid/midface of each specimen. Histologic examination of the anatomical location of hyaluronic acid gel was performed using hematoxylin and eosin and Hale colloidal iron stains. RESULTS: Histologic examination of the central and lateral lower eyelid/midface sections revealed a significant portion of hyaluronic acid gel in either a postorbicularis or a subcutaneous plane in 8 of 10 sections. Only 2 sections displayed hyaluronic acid gel solely within a preperiosteal plane. The medial sections revealed hyaluronic acid gel resting in either a preperiosteal or an intraorbicularis plane. Soft tissue structures such as deep fat compartment septa and the orbicularis oculi muscle appeared to play a significant role in influencing the resting position of hyaluronic acid gel. CONCLUSIONS: In most specimens, the location of a significant portion of hyaluronic acid gel following injection to the infraorbital hollows differed from the intended injection plane. Soft tissue structures including fat compartment septa and the orbicularis oculi muscle appear to influence the resting position of hyaluronic acid gel. Careful attention should be used to avoid overfilling the thin soft tissue layers of the medial infraorbital hollows or tear trough.

d(GGGT) 4 and r(GGGU) 4 are both HIV-1 inhibitors and interleukin-6 receptor aptamers.

Aptamers are oligonucleotides that bind targets with high specificity and affinity. They have become important tools for biosensing, target detection, drug delivery and therapy. We selected the quadruplex-forming 16-mer DNA aptamer AID-1 [d(GGGT) 4] with affinity for the interleukin-6 receptor (IL-6R) and identified single nucleotide variants that showed no significant loss of binding ability. The RNA counterpart of AID-1 [r(GGGU) 4] also bound IL-6R as quadruplex structure. AID-1 is identical to the well-known HIV inhibitor T30923, which inhibits both HIV infection and HIV-1 integrase. We also demonstrated that IL-6R specific RNA aptamers not only bind HIV-1 integrase and inhibit its 3' processing activity in vitro, but also are capable of preventing HIV de novo infection with the same efficacy as the established inhibitor T30175. All these aptamer target interactions are highly dependent on formation of quadruplex structure.

Patient preferences for community pharmacy asthma services: a discrete choice experiment.

BACKGROUND: Specialized community pharmacy services, involving the provision of disease state management and care by pharmacists, have been developed and trialled and have demonstrated very good health outcomes. Most of these services have been developed from a healthcare professional perspective. However, for the future uptake and long-term sustainability of these services as well as for better and sustained health outcomes for patients, it is vital to gain an understanding of patients' preferences. We can then structure healthcare services to match these preferences and needs rather than around clinical viewpoints alone. OBJECTIVE: The aim of this study was to elicit patient preferences for pharmacy-based specialized asthma services using a discrete choice experiment and to explore the value/importance that patients place on the different attributes of the asthma service. The existence of preference heterogeneity in the population was also investigated. METHODS: The study was conducted with asthma patients who had recently experienced a specialized asthma management service at their pharmacy in New South Wales, Australia. Pharmacists delivering the asthma service mailed out the discrete choice questionnaires to participating patients at the end of 6 months of service provision. A latent class (LC) model was used to investigate each patient's strength of preference and preference heterogeneity for several key attributes related to asthma service provision: frequency of visits, access to pharmacist, interaction with pharmacy staff, availability of a private area for consultation, provision of lung function testing, type and depth of advice provision, number of days with asthma symptoms and cost of service. RESULTS: Eighty useable questionnaires (of 170 questionnaires sent out) were received (response rate 47.1%). The study identified various key elements of asthma services important to patients. Further, the LC analysis revealed three classes with differing patient preferences for levels of asthma service provision. Patients in the Minimalistic Model class valued provision of lung function testing and preferred more frequent service visits. Cost of service had a negative effect on service preference for patients in this class. Patients in the Partial Model class mainly derived utility from the provision of lung function testing and comprehensive advice at the pharmacy and also wanted more frequent service visits. The Holistic Model class patients considered all attributes of the service to be important when making a choice. While the majority of the service attributes had a positive effect on preference for patients in this class, cost of service and days with symptoms of asthma had a negative effect on service preference. These patients also preferred fewer service visits. CONCLUSION: The study identified various key attributes that are important to patients with respect to community pharmacy-based asthma services. The results also demonstrate the existence of preference heterogeneity in the population. Asthma service providers need to take these findings into consideration in the design and development of future service models so as to increase their uptake and ensure their long-term sustainability.

IL-6 trans-signaling licenses mouse and human tumor microvascular gateways for trafficking of cytotoxic T cells.

Immune cells are key regulators of neoplastic progression, which is often mediated through their release of cytokines. Inflammatory cytokines such as IL-6 exert tumor-promoting activities by driving growth and survival of neoplastic cells. However, whether these cytokines also have a role in recruiting mediators of adaptive anticancer immunity has not been investigated. Here, we report that homeostatic trafficking of tumor-reactive CD8+ T cells across microvascular checkpoints is limited in tumors despite the presence of inflammatory cytokines. Intravital imaging in tumor-bearing mice revealed that systemic thermal therapy (core temperature elevated to 39.5°C ± 0.5°C for 6 hours) activated an IL-6 trans-signaling program in the tumor blood vessels that modified the vasculature such that it could support enhanced trafficking of CD8+ effector/memory T cells (Tems) into tumors. A concomitant decrease in tumor infiltration by Tregs during systemic thermal therapy resulted in substantial enhancement of Tem/Treg ratios. Mechanistically, IL-6 produced by nonhematopoietic stromal cells acted cooperatively with soluble IL-6 receptor-α and thermally induced gp130 to promote E/P-selectin- and ICAM-1-dependent extravasation of cytotoxic T cells in tumors. Parallel increases in vascular adhesion were induced by IL-6/soluble IL-6 receptor-α fusion protein in mouse tumors and patient tumor explants. Finally, a causal link was established between IL-6-dependent licensing of tumor vessels for Tem trafficking and apoptosis of tumor targets. These findings suggest that the unique IL-6-rich tumor microenvironment can be exploited to create a therapeutic window to boost T cell-mediated antitumor immunity and immunotherapy.

The transcription factor NFATc2 controls IL-6-dependent T cell activation in experimental colitis.

The nuclear factor of activated T cells (NFAT) family of transcription factors controls calcium signaling in T lymphocytes. In this study, we have identified a crucial regulatory role of the transcription factor NFATc2 in T cell-dependent experimental colitis. Similar to ulcerative colitis in humans, the expression of NFATc2 was up-regulated in oxazolone-induced chronic intestinal inflammation. Furthermore, NFATc2 deficiency suppressed colitis induced by oxazolone administration. This finding was associated with enhanced T cell apoptosis in the lamina propria and strikingly reduced production of IL-6, -13, and -17 by mucosal T lymphocytes. Further studies using knockout mice showed that IL-6, rather than IL-23 and -17, are essential for oxazolone colitis induction. Administration of hyper-IL-6 blocked the protective effects of NFATc2 deficiency in experimental colitis, suggesting that IL-6 signal transduction plays a major pathogenic role in vivo. Finally, adoptive transfer of IL-6 and wild-type T cells demonstrated that oxazolone colitis is critically dependent on IL-6 production by T cells. Collectively, these results define a unique regulatory role for NFATc2 in colitis by controlling mucosal T cell activation in an IL-6-dependent manner. NFATc2 in T cells thus emerges as a potentially new therapeutic target for inflammatory bowel diseases.

The IL-6/sIL-6R complex as a novel target for therapeutic approaches.

IL-6 plays a pivotal role in immune responses and certain oncologic conditions. The intense investigation of its biological activity and function led to the discovery of two different IL-6-driven signalling pathways. Binding to the membrane-bound IL-6 receptor (mIL-6R, CD126) causes the recruitment of two gp130 co-receptor molecules (CD130) and the activation of intracellular signalling cascades via gp130. Although this classical pathway is mainly limited to hepatocytes, neutrophils, monocytes/macrophages and certain other leukocyte populations, which express IL-6R on their surface, an alternative mechanism has also been described. Proteolytic cleavage of the mIL-6R protein or translation from alternatively spliced mRNA leads to the generation of a soluble form of the IL-6R (sIL-6R), which is likewise able to bind to IL-6. The resulting IL-6/sIL-6R complex is also capable of binding to gp130 and inducing intracellular signalling. Through this so-called 'trans-signalling' mechanism, IL-6 is able to stimulate cells that lack an endogenous mIL-6R. High levels of IL-6 and sIL-6R have been reported in several chronic inflammatory and autoimmune diseases as well as in cancer. Preclinical animal disease models have provided strong evidence that specific blockade of IL-6-regulated signalling pathways represents a promising approach for the therapy of these diseases. An optimised variant of the recently described fusion protein sgp30Fc is now heading towards its clinical evaluation.