Sustained Carbohydrate Antigen 19-9 Response to Neoadjuvant Chemotherapy in Borderline Resectable Pancreatic Cancer Predicts Progression and Survival.

BACKGROUND: As neoadjuvant therapy of borderline resectable pancreatic cancer (BRPC) is becoming more widely used, better indicators of progression are needed to help guide therapeutic decisions. MATERIALS AND METHODS: A retrospective review was performed on all patients with BRPC who received 24 weeks of neoadjuvant chemotherapy. Patients with chemotoxicity or medical comorbidities limiting treatment completion and nonexpressors of carbohydrate antigen 19-9 (CA19-9) were excluded. Serum CA19-9 response was analyzed as a predictor of disease progression, recurrence, and survival. RESULTS: One hundred four patients were included; 39 (37%) progressed on treatment (18 local and 21 distant) and 65 (63%) were resected (68% R0). Multivariate logistic regression analysis determined that the percent decrease in CA19-9 from baseline to minimum value (odds ratio [OR] 0.947, p ≤ .0001) and the percent increase from minimum value to final restaging CA19-9 (OR 1.030, p ≤ .0001) were predictive of progression. A receiver operating characteristics curve analysis determined cutoff values predictive of progression, which were used to create four prognostic groups. CA19-9 responses were categorized as follows: (1) always normal (n = 6); (2) poor response (n = 31); (3) unsustained response (n = 19); and (4) sustained response (n = 48). Median overall survival for Groups 1-4 was 58, 16, 20, and 38 months, respectively (p ≤ .0001). CONCLUSION: Patients with initially elevated CA19-9 levels who do not have a decline to a sustained low level are at risk for progression, recurrence, and poor survival. Alternative treatment strategies prior to an attempt at curative resection should be considered in this cohort. IMPLICATIONS FOR PRACTICE: This study identified percent changes in carbohydrate antigen 19-9 blood levels while on chemotherapy that predict tumor growth in patients with advanced pancreas cancer. These changes could be used to better select patients who would benefit from surgical removal of their tumors and improve survival.

Correction to: Developing vaccines against epidemic-prone emerging infectious diseases.

In the original publication of this article, the author name Richard Hatchett was incorrectly published.

Developing vaccines against epidemic-prone emerging infectious diseases.

Today's world is characterized by increasing population density, human mobility, urbanization, and climate and ecological change. This global dynamic has various effects, including the increased appearance of emerging infectious diseases (EIDs), which pose a growing threat to global health security.Outbreaks of EIDs, like the 2013-2016 Ebola outbreak in West Africa or the current Ebola outbreak in Democratic Republic of the Congo (DRC), have not only put populations in low- and middle-income countries (LMIC) at risk in terms of morbidity and mortality, but they also have had a significant impact on economic growth in affected regions and beyond.The Coalition for Epidemic Preparedness Innovation (CEPI) is an innovative global partnership between public, private, philanthropic, and civil society organizations that was launched as the result of a consensus that a coordinated, international, and intergovernmental plan was needed to develop and deploy new vaccines to prevent future epidemics.CEPI is focusing on supporting candidate vaccines against the World Health Organization (WHO) Blueprint priority pathogens MERS-CoV, Nipah virus, Lassa fever virus, and Rift Valley fever virus, as well as Chikungunya virus, which is on the WHO watch list. The current vaccine portfolio contains a wide variety of technologies, ranging across recombinant viral vectors, nucleic acids, and recombinant proteins. To support and accelerate vaccine development, CEPI will also support science projects related to the development of biological standards and assays, animal models, epidemiological studies, and diagnostics, as well as build capacities for future clinical trials in risk-prone contexts.

Filarial infection modulates the immune response to Mycobacterium tuberculosis through expansion of CD4+ IL-4 memory T cells.

Exaggerated CD4(+) T helper 2-specific cytokine producing memory T cell responses developing concomitantly with a T helper 1 response might have a detrimental role in immunity to infection caused by Mycobacterium tuberculosis. To assess the dynamics of Ag-specific memory T cell compartments in the context of filarial infection, we used multiparameter flow cytometry on PBMCs from 25 microfilaremic filarial-infected (Inf) and 14 filarial-uninfected (Uninf) subjects following stimulation with filarial Ag (BmA) or with the M. tuberculosis-specific Ag culture filtrate protein-10 (CFP-10). Our data demonstrated that the Inf group had a marked increase in BmA-specific CD4(+)IL-4(+) cells (median net frequency compared with baseline [Fo] = 0.09% versus 0.01%; p = 0.038) but also to CFP-10 (Fo = 0.16% versus 0.007%; p = 0.04) and staphylococcal enterotoxin B (Fo = 0.49% versus 0.26%; p = 0.04). The Inf subjects showed a BmA-specific expansion of CD4(+)CD45RO(+)IL-4(+) producing central memory (TCM, CD45RO(+)CCR7(+)CD27(+); Fo = 1.1% versus 0.5%; p = 0.04) as well as effector memory (TEM, CD45RO(+)CCR7(-)CD27(-); Fo = 1.5% versus 0.2%; p = 0.03) with a similar but nonsignificant response to CFP-10. In addition, there was expansion of CD4(+)IL-4(+)CD45RA(+)CCR7(+)CD27(+) (naive-like) in Inf individuals compared with Uninf subjects. Among Inf subjects with definitive latent tuberculosis, there were no differences in frequencies of IL-4-producing cells within any of the memory compartments compared with the Uninf group. Our data suggest that filarial infection induces Ag-specific, exaggerated IL-4 responses in distinct T cell memory compartments to M. tuberculosis-specific Ags, which are attenuated in subjects who are able to mount a delayed type hypersensitivity reaction to M. tuberculosis.

Maternal Helminth Infection Is Associated With Higher Infant Immunoglobulin A Titers to Antigen in Orally Administered Vaccines.

BACKGROUND: Many studies have documented lower vaccine efficacy among children in low-income countries, compared with their counterparts in high-income countries. This disparity is especially apparent with respect to oral vaccines such as rotavirus and oral polio vaccines. One potential contributing factor is the presence of maternal antenatal helminth infections, which can modulate the infant's developing immune system. METHODS: Using a multiplex immunoassay, we tested plasma immunoglobulin A (IgA) or immunoglobulin G (IgG) levels specific for antigens in 9 routinely administered childhood vaccines among 1639 children aged approximately 13 months enrolled in the ECUAVIDA (Ecuador Life) birth cohort study in Ecuador. We compared vaccine responses in 712 children of mothers who tested positive for helminth infections in the last trimester of pregnancy to responses in 927 children of mothers without helminth infection. RESULTS: Plasma IgA levels specific for antigens in rotavirus vaccine and oral polio vaccine containing poliovirus serotypes 1 and 3 were all significantly higher in children of helminth-infected mothers, compared with children of uninfected mothers. Plasma IgG levels specific for diphtheria, tetanus, pertussis, measles, rubella, and Haemophilus influenzae type b vaccine antigens were comparable between the 2 groups. CONCLUSIONS: Antenatal maternal helminth infections were not associated with reduced antibody responses to infant vaccines, but rather with modestly increased IgA responses to oral vaccines.

Driving consistency: CEPI-Centralized Laboratory Network's conversion factor initiative for SARS-CoV-2 clinical assays used for efficacy assessment of COVID vaccines.

To date, thousands of SARS-CoV-2 samples from many vaccine developers have been tested within the CEPI-Centralized Laboratory Network. To convert data from each clinical assay to international standard units, the WHO international standard and the CEPI standard generated by the Medicines and Healthcare products Regulatory Agency were run in multiple facilities to determine the conversion factor for each assay. Reporting results in international units advances global understanding of SARS-CoV-2 immunity and vaccine efficacy, enhancing the quality, reliability, and utility of clinical assay data.

Rapid diagnostic test: a critical need for outbreak preparedness and response for high priority pathogens.

Rapid diagnostic tests (RDTs) are critical for preparedness and response against an outbreak or pandemic and have been highlighted in the 100 Days Mission, a global initiative that aims to prepare the world for the next epidemic/pandemic by driving the development of diagnostics, vaccines and therapeutics within 100 days of recognition of a novel Disease X threat.RDTs play a pivotal role in early case identification, surveillance and case management, and are critical for initiating deployment of vaccine and monoclonal antibodies. Currently available RDTs, however, have limited clinical sensitivity and specificity and inadequate validation. The development, validation and implementation of RDTs require adequate and sustained financing from both public and private sources. While the World Health Assembly recently passed a resolution on diagnostic capacity strengthening that urges individual Member States to commit resources towards this, the resolution is not binding and implementation will likely be impeded by limited financial resources and other competing priorities, particularly in low-income countries. Meanwhile, the diagnostic industry has not sufficiently invested in RDT development for high priority pathogens.Currently, vaccine development projects are getting the largest funding support among medical countermeasures. Yet vaccines are insufficient tools in isolation, and pandemic preparedness will be incomplete without parallel investment in diagnostics and therapeutics.The Pandemic Fund, a global financing mechanism recently established for strengthening pandemic prevention, preparedness and response, may be a future avenue for supporting diagnostic development.In this paper, we discuss why RDTs are critical for preparedness and response. We also discuss RDT investment challenges and reflect on the way forward.

Inactivation of the UL37 Deamidase Enhances Virus Replication and Spread of the HSV-1(VC2) Oncolytic Vaccine Strain and Secretion of GM-CSF.

The HSV-1 (VC2) live-attenuated vaccine strain was engineered with specific deletions in the amino termini of glycoprotein K (gK) and membrane protein UL20, rendering the virus unable to enter neurons and establish latency. VC2 replicates efficiently in epithelial cell culture but produces lower viral titers and smaller viral plaques than its parental HSV-1 (F) wild-type virus. VC2 is an effective live-attenuated vaccine against HSV-1 and HSV-2 infections in mice and guinea pigs and an anti-tumor immunotherapeutic and oncolytic virus against melanoma and breast cancer in mouse models. Previously, we reported that the gK/UL20 complex interacts with the UL37 tegument protein, and this interaction is essential for virion intracellular envelopment and egress. To investigate the potential role of the UL37 deamidase functions, the recombinant virus FC819S and VC2C819S were constructed with a C819S substitution to inactivate the UL37 predicted deamidase active site on an HSV-1(F) and HSV-1(VC2) genetic background, respectively. FC819S replicated to similar levels with HSV-1(F) and produced similar size viral plaques. In contrast, VC2C819S replication was enhanced, and viral plaques increased in size, approaching those of the wild-type HSV-1(F) virus. FC819S infection of cell cultures caused enhanced GM-CSF secretion in comparison to HSV-1(F) across several cell lines, including HEp2 cells and cancer cell lines, DU145 (prostate) and Panc 04.03 (pancreas), and primary mouse peritoneal cells. VC2 infection of these cell lines caused GM-CSF secretion at similar levels to FC819S infection. However, the VC2C819S virus did not exhibit any further enhancement of GM-CSF secretion compared to the VC2 virus. These results suggest that the UL37 deamidation functions in conjunction with the gK/UL20 complex to facilitate virus replication and GM-CSF secretion.

Text Messages to Support Caregivers in a Health Care System: Development and Pilot and National Rollout Evaluation.

BACKGROUND: Although there are many interventions to support caregivers, SMS text messaging has not been used widely. OBJECTIVE: In this paper, we aimed to describe development of the Department of Veterans Affairs (VA) Annie Stress Management SMS text messaging protocol for caregivers of veterans, its pilot test, and subsequent national rollout. METHODS: The stress management protocol was developed with text messages focusing on education, motivation, and stress-alleviating activities based on the Resources for Enhancing All Caregivers Health (REACH) VA caregiver intervention. This protocol was then tested in a pilot study. On the basis of the pilot study results, a national rollout of the protocol was executed and evaluated. Caregivers were referred from VA facilities nationally for the pilot and national rollout. Pilot caregivers were interviewed by telephone; national rollout caregivers were sent a web-based evaluation link at 6 months. For both evaluations, questions were scored on a Likert scale ranging from completely disagree to completely agree. For both the pilot and national rollout, quantitative data were analyzed with frequencies and means; themes were identified from open-ended qualitative responses. RESULTS: Of the 22 caregivers in the pilot study, 18 (82%) provided follow-up data. On a 5-point scale, they reported text messages had been useful in managing stress (mean score 3.8, SD 1.1), helping them take care of themselves (mean score 3.7, SD 1.3), and making them feel cared for (mean score 4.1, SD 1.7). Texts were easy to read (mean score 4.5, SD 1.2), did not come at awkward times (mean score 2.2, SD 1.4), were not confusing (mean score 1.1, SD 0.2), and did not cause problems in responding (mean score 1.9, 1.1); however, 83% (15/18) of caregivers did not want to request an activity when stressed. Consequently, the national protocol did not require caregivers to respond. In the national rollout, 22.17% (781/3522) of the eligible caregivers answered the web-based survey and reported that the messages had been useful in managing stress (mean score 4.3, SD 0.8), helping them take care of themselves (mean score 4.3, SD 0.8) and loved ones (mean score 4.2, SD 0.8), and making them feel cared for (mean score 4.5, SD 0.8). Almost two-thirds (509/778, 65.4%) of the participants tried all or most of the strategies. A total of 5 themes were identified. The messages were appreciated, helped with self-care, and made them feel less alone, looking on Annie as a friend. The caregivers reported that the messages were on target and came when they were most needed and did not want them to stop. This success has led to four additional caregiver texting protocols: bereavement, dementia behaviors and stress management, (posttraumatic stress disorder) PTSD behaviors, and taking care of you, with 7274 caregivers enrolled as of February 2022. CONCLUSIONS: Caregivers reported the messages made them feel cared for and more confident. SMS text messaging, which is incorporated into clinical settings and health care systems, may represent a low-cost way to provide useful and meaningful support to caregivers.

Predicted Structure and Functions of the Prototypic Alphaherpesvirus Herpes Simplex Virus Type-1 UL37 Tegument Protein.

The alphaherpesvirus UL37 tegument protein is a highly conserved, multi-functional protein. Mutagenesis analysis delineated the UL37 domains necessary for retrograde transport and viral replication. Specifically, the amino-terminal 480 amino acids are dispensable for virus replication in epithelial cell culture, but it is unknown whether this amino-terminal deletion affects UL37 structure and intracellular transport in epithelial cells and neurons. To investigate the structure and function of UL37, we utilized multiple computational approaches to predict and characterize the secondary and tertiary structure and other functional features. The structure of HSV-1 UL37 and Δ481N were deduced using publicly available predictive algorithms. The predicted model of HSV-1 UL37 is a stable, multi-functional, globular monomer, rich in alpha helices, with unfolded regions within the linker and the C-tail domains. The highly flexible C-tail contains predicted binding sites to the dynein intermediate chain, as well as DNA and RNA. Predicted interactions with the cytoplasmic surface of the lipid membrane suggest UL37 is a peripheral membrane protein. The Δ481N truncation did not alter the predicted structure of the UL37 C-terminus protein and its predicted interaction with dynein. We validated these models by examining the replication kinetics and transport of the Δ481N virus toward the nuclei of infected epithelial and neuronal cells. The Δ481N virus had substantial defects in virus spread; however, it exhibited no apparent defects in virus entry and intracellular transport. Using computational analyses, we identified several key features of UL37, particularly the flexible unstructured tail; we then demonstrated that the UL37 C-terminus alone is sufficient to effectively transport the virus towards the nucleus of infected epithelial and neuronal cells.

Opportunities for Refinement of Non-Human Primate Vaccine Studies.

Non-human primates (NHPs) are used extensively in the development of vaccines and therapeutics for human disease. High standards in the design, conduct, and reporting of NHP vaccine studies are crucial for maximizing their scientific value and translation, and for making efficient use of precious resources. A key aspect is consideration of the 3Rs principles of replacement, reduction, and refinement. Funders of NHP research are placing increasing emphasis on the 3Rs, helping to ensure such studies are legitimate, ethical, and high-quality. The UK's National Centre for the 3Rs (NC3Rs) and the Coalition for Epidemic Preparedness Innovations (CEPI) have collaborated on a range of initiatives to support vaccine developers to implement the 3Rs, including hosting an international workshop in 2019. The workshop identified opportunities to refine NHP vaccine studies to minimize harm and improve welfare, which can yield better quality, more reproducible data. Careful animal selection, social housing, extensive environmental enrichment, training for cooperation with husbandry and procedures, provision of supportive care, and implementation of early humane endpoints are features of contemporary good practice that should and can be adopted more widely. The requirement for high-level biocontainment for some pathogens imposes challenges to implementing refinement but these are not insurmountable.

Two Sides to Every Story: Herpes Simplex Type-1 Viral Glycoproteins gB, gD, gH/gL, gK, and Cellular Receptors Function as Key Players in Membrane Fusion.

Herpes simplex virus type-1 (HSV-1) and type-2 (HSV-2) are prototypical alphaherpesviruses that are characterized by their unique properties to infect trigeminal and dorsal root ganglionic neurons, respectively, and establish life-long latent infections. These viruses initially infect mucosal epithelial tissues and subsequently spread to neurons. They are associated with a significant disease spectrum, including orofacial and ocular infections for HSV-1 and genital and neonatal infections for HSV-2. Viral glycoproteins within the virion envelope bind to specific cellular receptors to mediate virus entry into cells. This is achieved by the fusion of the viral envelope with the plasma membrane. Similarly, viral glycoproteins expressed on cell surfaces mediate cell-to-cell fusion and facilitate virus spread. An interactive complex of viral glycoproteins gB, gD/gH/gL, and gK and other proteins mediate these membrane fusion phenomena with glycoprotein B (gB), the principal membrane fusogen. The requirement for the virion to enter neuronal axons suggests that the heterodimeric protein complex of gK and membrane protein UL20, found only in alphaherpesviruses, constitute a critical determinant for neuronal entry. This hypothesis was substantiated by the observation that a small deletion in the amino terminus of gK prevents entry into neuronal axons while allowing entry into other cells via endocytosis. Cellular receptors and receptor-mediated signaling synergize with the viral membrane fusion machinery to facilitate virus entry and intercellular spread. Unraveling the underlying interactions among viral glycoproteins, envelope proteins, and cellular receptors will provide new innovative approaches for antiviral therapy against herpesviruses and other neurotropic viruses.

Status Report on COVID-19 Vaccines Development.

PURPOSE OF REVIEW: The emergence of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has affected lives of billions of individuals, globally. There is an urgent need to develop interventions including vaccines to control the ongoing pandemic. RECENT FINDINGS: Development of tools for fast-tracked testing including small and large animal models for vaccine efficacy analysis, assays for immunogenicity assessment, critical reagents, international biological standards, and data sharing allowed accelerated development of vaccines. More than 300 vaccines are under development and 9 of them are approved for emergency use in various countries, with impressive efficacy ranging from 50 to 95%. Recently, several new SARS-CoV-2 variants have emerged and are circulating globally, and preliminary findings imply that some of them may escape immune responses against previous variants and diminish efficacy of current vaccines. Most of these variants acquired new mutations in their surface protein (Spike) which is the antigen in most of the approved/under development vaccines. SUMMARY: In this review, we summarize novel and traditional approaches for COVID-19 vaccine development including inactivated, attenuated, nucleic acid, vector and protein based. Critical assessment of humoral and cell-mediated immune responses induced by vaccines has shown comparative immunogenicity profiles of various vaccines in clinical phases. Recent reports confirmed that some currently available vaccines provide partial to complete protection against emerging SARS-CoV-2 variants. If more mutated variants emerge, current vaccines might need to be updated accordingly either by developing vaccines matching the circulating strain or designing multivalent vaccines to extend the breadth.

An Exploration across Institution Types of Undergraduate Life Sciences Student Decisions to Stay in or Leave an Academic-Year Research Experience.

Undergraduate research is one of the most valuable activities an undergraduate can engage in because of its benefits, and studies have shown that longer experiences are more beneficial. However, prior research has illuminated that undergraduates encounter challenges that may cause them to exit research prematurely. These studies have been almost exclusively conducted at research-intensive (R1) institutions, and it is unclear whether such challenges are generalizable to other institution types. To address this, we extended a study previously conducted at public R1 institutions. In the current study, we analyze data from 1262 students across 25 public R1s, 12 private R1s, 30 master's-granting institutions, and 20 primarily undergraduate institutions (PUIs) to assess 1) to what extent institution type predicts students' decisions to persist in undergraduate research and 2) what factors affect students' decisions to either stay in or consider leaving their undergraduate research experiences (UREs) at different institution types. We found students at public R1s are more likely to leave their UREs compared with students at master's-granting institutions and PUIs. However, there are few differences in why students enrolled at different institution types consider leaving or choose to stay in their UREs. This work highlights the importance of studying undergraduate research across institutions.

Impact of Type 1 Diabetes Mellitus on Skeletal Integrity and Strength in Adolescents as Assessed by HRpQCT.

Adults with type 1 diabetes mellitus (T1DM) are at risk of premature osteoporosis and fractures. The onset of T1DM typically starts during childhood and adolescence. Thus, the effects of DM on the skeleton may be established during this period. Studies in children with T1DM primarily use DXA with conflicting results. We present the first study in adolescents assessing the impact of T1DM on skeletal microstructure and strength using HRpQCT. We recruited 22 patients aged 12 to 16 years with T1DM who were matched by age, gender, and pubertal stage with healthy controls. Paired t tests were applied to assess differences in cortical and trabecular microarchitecture measurements from HRpQCT, and skeletal strength from HRpQCT-derived microfinite element analysis. Subtotal body, lumbar, and pelvic parameters were assessed using DXA. There was no significant difference in subtotal body, lumbar spine, and pelvic BMD between T1DM and control pairs. However, tibial trabecular thickness was lower (-0.005 mm; 95% CI, -0.01 to -0.001; p = 0.029) and trabecular loading was lower at the distal radius (ratio of the load taken by the trabecular bone in relation to the total load at the distal end (Tb.F/TF) distal: -6.2; 95% CI, -12.4 to -0.03; p = 0.049), and distal and proximal tibia (Tb.F/TF distal: -5.2, 95% CI, -9.2 to -1.2; p = 0.013; and Tb.F/TF proximal: -5.0, 95% CI, -9.8 to -0.1; p = 0.047) in T1DM patients. A subanalysis of radial data of participants with duration of T1DM of at least 2 years and their matched controls demonstrated a reduced trabecular bone number (-0.15, 95% CI, -0.26 to -0.04; p = 0.012), increased trabecular separation (0.041 mm, 95% CI, 0.009-0.072; p = 0.015), an increased trabecular inhomogeneity (0.018, 95% CI, 0.003-0.034; p = 0.021). Regression models demonstrated a reduction in tibial stiffness (-0.877 kN/mm; p = 0.03) and tibial failure load (-0.044 kN; p = 0.03) with higher HbA1C. Thus, in adolescents with T1DM, detrimental changes are seen in tibial and radial microarchitecture and tibial and radial strength before changes in DXA occur and may result from poor diabetic control. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Rational development of a high-affinity secretin receptor antagonist.

The secretin receptor is a prototypic class B GPCR with substantial and broad pharmacologic importance. The aim of this project was to develop a high affinity selective antagonist as a new and important pharmacologic tool and to aid stabilization of this receptor in an inactive conformation for ultimate structural characterization. Amino-terminal truncation of the natural 27-residue ligand reduced biological activity, but also markedly reduced binding affinity. This was rationally and experimentally overcome with lactam stabilization of helical structure and with replacement of residues with natural and unnatural amino acids. A key new step in this effort was the replacement of peptide residue Leu22 with L-cyclohexylalanine (Cha) to enhance potential hydrophobic interactions with receptor residues Leu31, Val34, and Phe92 that were predicted from molecular modeling. Alanine-replacement mutagenesis of these residues markedly affected ligand binding and biological activity. The optimal antagonist ligand, (Y10,c[E16,K20],I17,Cha22,R25)sec(6-27), exhibited high binding affinity (4 nM), similar to natural secretin, and exhibited no demonstrable biological activity to stimulate cAMP accumulation, intracellular calcium mobilization, or ß-arrestin-2 translocation. It acts as an orthosteric competitive antagonist, predicted to bind within the peptide-binding groove in the receptor extracellular domain. The analogous peptide that was one residue longer, retaining Thr5, exhibited partial agonist activity, while further truncation of even a single residue (Phe6) reduced binding affinity. This sec(6-27)-based peptide will be an important new tool for pharmacological and structural studies.

The honeypot study protocol: a randomized controlled trial of exit-site application of medihoney antibacterial wound gel for the prevention of catheter-associated infections in peritoneal dialysis patients.

OBJECTIVES: The primary objective of this study is to determine whether daily exit-site application of standardized antibacterial honey (Medihoney Antibacterial Wound Gel; Comvita, Te Puke, New Zealand) results in a reduced risk of catheter-associated infections in peritoneal dialysis (PD) patients compared with standard topical mupirocin prophylaxis of nasal staphylococcal carriers. DESIGN: Multicenter, prospective, open label, randomized controlled trial. SETTING: PD units throughout Australia and New Zealand. PARTICIPANTS: The study will include both incident and prevalent PD patients (adults and children) for whom informed consent can be provided. Patients will be excluded if they have had (1) a history of psychological illness or condition that interferes with their ability to understand or comply with the requirements of the study; (2) recent (within 1 month) exit-site infection, peritonitis, or tunnel infection; (3) known hypersensitivity to, or intolerance of, honey or mupirocin; (4) current or recent (within 4 weeks) treatment with an antibiotic administered by any route; or (5) nasal carriage of mupirocin-resistant Staphylococcus aureus. METHODS: 370 subjects will be randomized 1:1 to receive either daily topical exit-site application of Medihoney Antibacterial Wound Gel (all patients) or nasal application of mupirocin if staphylococcal nasal carriage is demonstrated. All patients in the control and intervention groups will perform their usual exit-site care according to local practice. The study will continue until 12 months after the last patient is recruited (anticipated recruitment time is 24 months). MAIN OUTCOME MEASURES: The primary outcome measure will be time to first episode of exit-site infection, tunnel infection, or peritonitis, whichever comes first. Secondary outcome measures will include time to first exit-site infection, time to first tunnel infection, time to first peritonitis, time to infection-associated catheter removal, catheter-associated infection rates, causative organisms, incidence of mupirocin-resistant microbial isolates, and other adverse reactions. CONCLUSIONS: This multicenter Australian and New Zealand study has been designed to provide evidence to help nephrologists and their PD patients determine the optimal strategy for preventing PD catheter-associated infections. Demonstration of a significant improvement in PD catheter-associated infections with topical Medihoney will provide clinicians with an important new prophylactic strategy with a low propensity for promoting antimicrobial resistance.

Dynamics of the immune reaction to pancreatic cancer from inception to invasion.

The dynamics of cancer immunosurveillance remain incompletely understood, hampering efforts to develop immunotherapy of cancer. We evaluated the evolving in vivo immune response to a spontaneous tumor in a genetically defined mouse model of pancreatic ductal adenocarcinoma from the inception of preinvasive disease to invasive cancer. We observed a prominent leukocytic infiltration even around the lowest grade preinvasive lesions, but immunosuppressive cells, including tumor-associated macrophages, myeloid-derived suppressor cells (MDSC), and regulatory T cells (Treg), dominated the early response and persisted through invasive cancer. Effector T cells, however, were scarce in preinvasive lesions, found in only a subset of advanced cancers, and showed no evidence of activation. The lack of tumor-infiltrating effector T cells strongly correlated with the presence of intratumoral MDSC with a near mutual exclusion. In vitro, we found that MDSC suppressed T-cell proliferation. Overall, our results show that suppressive cells of the host immune system appear early during pancreatic tumorigenesis, preceding and outweighing antitumor cellular immunity, and likely contribute to disease progression. Thus, in contrast to the hypothesis that an early "elimination phase" of cancer immunosurveillance is eventually overwhelmed by a growing invasive tumor, our findings suggest that productive tumor immunity may be undermined from the start. Efforts to test potent inhibitors of MDSC, tumor-associated macrophages, and Treg, particularly early in the disease represent important next steps for developing novel immunotherapy of cancer.

Factors that predict life sciences student persistence in undergraduate research experiences.

Undergraduate research experiences (UREs) have the potential to benefit undergraduates and longer UREs have been shown to lead to greater benefits for students. However, no studies have examined what causes students to stay in or consider leaving their UREs. In this study, we examined what factors cause students to stay in their UREs, what factors cause students to consider leaving their UREs, and what factors cause students to leave their UREs. We sampled from 25 research-intensive (R1) public universities across the United States and surveyed 768 life sciences undergraduates who were currently participating in or had previously participated in a URE. Students answered closed-ended and open-ended questions about factors that they perceived influenced their persistence in UREs. We used logistic regression to explore to what extent student demographics predicted what factors influenced students to stay in or consider leaving their UREs. We applied open-coding methods to probe the student-reported reasons why students chose to stay in and leave their UREs. Fifty percent of survey respondents considered leaving their URE, and 53.1% of those students actually left their URE. Students who reported having a positive lab environment and students who indicated enjoying their everyday research tasks were more likely to not consider leaving their UREs. In contrast, students who reported a negative lab environment or that they were not gaining important knowledge or skills were more likely to leave their UREs. Further, we identified that gender, race/ethnicity, college generation status, and GPA predicted which factors influenced students' decisions to persist in their UREs. This research provides important insight into how research mentors can create UREs that undergraduates are willing and able to participate in for as long as possible.

Respiratory Syncytial Virus Vaccine Approaches: a Current Overview.

PURPOSE OF REVIEW: Respiratory syncytial virus (RSV) is a global human pathogen responsible for lower respiratory tract infections (LRTI). While RSV infection is innocuous in healthy adults, it is the leading cause of infant hospitalization for respiratory tract infection. Nearly everyone shows evidence of an RSV infection by the age of 3. However, there is still not a vaccine commercially available. This review will provide an update on the clinical and preclinical vaccine studies and different approaches to prevent RSV infection. RECENT FINDINGS: Novel vaccine approaches that induce protection against RSV without enhancement of respiratory tract disease. SUMMARY: Recent technological approaches have led to generation of different strategies to prevent RSV infection, including live attenuated, chimeric, and subunit vaccines, virus-like particles, and nanoparticles. These vaccine approaches represent promising candidates towards an efficient RSV vaccine that effectively protects infants, children, and adults.