Improving First Case Operating Room Efficiency.

INTRODUCTION: Improving transition to the operating room (OR) can enhance healthcare efficiency. Our aim was to determine whether adopting a communication board (CB) for first case surgical patients reduced delays to OR. METHODS: A retrospective observational study was conducted from April to October 2021. We calculated differences in surgical daycare (SDC) departure time before and after implementation of the CB, differences in departure whether the CB was used or not, delay in variability between surgical specialties, and overall adoption of the CB. RESULTS: After CB adoption, 13% of first cases left SDC by predefined target times. The mean delay in transfer was 18:51 minutes. When the CB was used, cases were on average 10:43 late, compared with 26:00 when it was not used. Otolaryngology had the shortest delays while plastic surgery had the longest. Reasons for delays included staffing delays, holds, and pending laboratory results. CONCLUSIONS: Introducing a CB significantly reduced delays in transferring first case surgical patients from SDC to the OR.

Beyond Skin Deep: case-based online modules to teach multidisciplinary care in dermatology among clerkship students.

BACKGROUND: Canadian medical schools offer limited clinical dermatology training. In addition, there is a lack of educational resources that are designed specifically for clerkship students that focus on the multidisciplinary nature of dermatology. OBJECTIVES: After developing case-based educational resources to address the lack of clinical exposure and learning of multidisciplinary care in dermatology, this study aimed to evaluate the educational intervention and gather feedback for future module development. METHODS: Ten online interactive dermatology case-based modules involving 14 other disciplines were created. Medical students (n = 89) from two Canadian schools were surveyed regarding perceptions of the existing dermatology curriculum. Among 89 students, 46 voluntarily completed the modules, and a survey (a five-point Likert scale ratings) including narrative feedback was provided to determine an improvement in dermatology knowledge and understanding of multidisciplinary care. RESULTS: Among 89 surveyed students, only 17.1% agreed that their pre-clerkship dermatology education was sufficient and 10.2% felt comfortable managing patients with skin conditions in a clinical setting. Among 46 students, 95.7% of students agreed that the modules fit their learning style (4.17 ± 0.73 on Likert scale) with positive narrative feedback. 91.3% agreed or strongly agreed that the modules enhanced their dermatology knowledge (4.26 ± 0.61). 79.6% of students agreed that the modules helped with understanding the multidisciplinary nature of dermatological cases (3.98 ± 0.81). Student comfort to manage skin conditions increased 7.7 times from 10.2% to 78.3% post-module. CONCLUSIONS: Clerkship students had limited knowledge of dermatologic conditions; the case-based modules were able to successfully address these deficits and assist students in understanding the multidisciplinary nature of dermatology.

Adherence to Surveillance Endoscopies Posteradication of Barrett's Esophagus With High-grade Dysplasia or Carcinoma In Situ.

GOALS: We aimed to evaluate factors associated with patient adherence to recommended surveillance guidelines during the first 3 years after endoscopic eradication of Barrett's esophagus (BE) with high-grade dysplasia (HGD) or T1a carcinoma in situ (CIS) and the relationship between adherence and detection of recurrence. BACKGROUND: While surveillance endoscopies after treatment of BE with HGD or T1a CIS are an important component of therapy, it is unclear whether these high-risk patients are adhering to recommended surveillance guidelines. MATERIALS AND METHODS: A total of 123 BE patients who underwent radiofrequency ablation±endoscopic mucosal resection for biopsy-proven HGD, or CIS between January 2010 and November 2018 underwent retrospective review for adherence to surveillance guidelines, patient factors related to adherence, and recurrence of dysplasia or CIS at 12, 24, and 36 months. RESULTS: Of 123 BE patients (89 HGD and 34 CIS), adherence during the first year following treatment was 26.97% for HGD patients and 41.18% for CIS patients, with increasing adherence rates in subsequent years. Patients who received 3 to 4 surveillance endoscopies in the first year posttreatment had significantly higher rates of recurrence detection than patients who received 0 to 2 surveillance endoscopies over this interval ( P =0.01). No patient factors were found to impact adherence significantly. CONCLUSIONS: Adherence to recommended surveillance intervals after endoscopic treatment of BE with HGD or CIS is low, with poor adherence during the first year associated with decreased detection of recurrence. Future studies are needed to evaluate risk factors and develop a potential intervention for poor adherence in this high-risk population.

Parent Emotion Talk with Preschoolers from Low-Income Mexican American and Chinese American Families: Links to Sociocultural Factors.

Emotion talk (ET), an emotion socialization practice theorized to promote children's emotion understanding and emotion regulation, has been linked to better socioemotional adjustment in diverse samples. Immigrant children face developmentally unique challenges and opportunities related to their multi-lingual and multi-cultural experiences. The present study aimed to identify sociocultural correlates of parent ET in two groups of low-income immigrant families with preschool-age children: Mexican American (MA) and Chinese American (CA) families. In 90 parent-child dyads (child age = 38 to 70 months, 59% girls; 46 Mexican American and 44 Chinese American) recruited from Head Start programs, parents' (mostly mothers') ET quality and quantity (i.e., use of emotion words, emotion questions and explanations, and overall elaborateness of ET) were coded from verbal transcripts of a shared picture book reading task. First, we found similarities and differences in ET across the two groups. Both MA and CA parents used emotion words, emotion questions, and emotion reasoning, whereas linking the story to personal emotion experience was infrequent. MA parents used more negative emotion words, emotion reasoning, and engaged in more elaborate ET than CA parents. Second, we examined the unique relations of multiple socio-cultural factors (SES, cultural orientations, parent and child demographics) to parent ET. Parent education and child age were associated positively with emotion questions, income was associated positively with emotion reasoning, and parents' heritage culture orientation was associated positively with the elaborateness of ET. The findings highlight the need to consider socio-cultural variations in emotion socialization practices when adapting and disseminating socioemotional learning interventions.

Teachers' Language Use in Multilingual Head Start Classrooms: Implications for Dual Language Learners.

Dual language learners (DLLs) are sensitive to teachers' language influence in early childhood classrooms. In this mixed methods study incorporating 53 teachers from 28 preschools in Northern California, we investigated the characteristics of teachers' language use in preschools teaching Chinese-English and Spanish-English DLLs. We further examined the links of teachers' language use to the DLLs' expressive vocabulary in English and their heritage language (HL), controlling for home language exposure and other confounding variables. Finally, we conducted interviews with teachers to understand how they make meaning of their daily language practices. The sample of children consisted of 190 Chinese-English (N = 125) and Spanish-English (N = 65) DLLs (mean age = 48.3 months; 48% females). The teacher survey showed that most teachers spoke two or more languages and used a mix of English and their HL during their interactions with DLLs. The results of random-intercept models showed that teachers' language use did not uniquely predict children's vocabulary, controlling for family-level factors. However, the teachers with more years of teaching DLLs oversaw children with a higher HL vocabulary. The interview data revealed that teachers employ several strategies to communicate with DLLs and support HL maintenance. Our study reveals the multilingual backgrounds of preschool teachers and the rich language strategies they implement in multilingual classrooms. Future directions concerning the quality and development of teachers' language use are discussed.

Common Sleep Disorders in Pregnancy.

Compared with men, women have a greater risk of sleep disorders and report higher rates of sleep disturbance. Hormonal and physiologic changes throughout the life span appear to influence a woman's ability to get a good night's sleep. Sleep disturbances are commonly reported during pregnancy, affecting more than one-half of all pregnancies and increasing as gestation progresses. The pervasiveness of sleep complaints during pregnancy may lead to a belief that these symptoms are normal or to be expected. Unfortunately, this perception may impede the accurate diagnosis of sleep disorders during this crucial time. Obstructive sleep apnea, insomnia, and restless legs syndrome are the most common sleep disorders in pregnancy. Sleep disruption in pregnancy can substantially worsen maternal quality of life and may be a risk factor for adverse pregnancy outcomes. This review outlines important considerations for obstetricians taking care of pregnant patients with sleep-related complaints.

Comparative Transcriptomics Reveals Distinct Patterns of Gene Expression Conservation through Vertebrate Embryogenesis.

Despite life's diversity, studies of variation often remind us of our shared evolutionary past. Abundant genome sequencing and analyses of gene regulatory networks illustrate that genes and entire pathways are conserved, reused, and elaborated in the evolution of diversity. Predating these discoveries, 19th-century embryologists observed that though morphology at birth varies tremendously, certain stages of vertebrate embryogenesis appear remarkably similar across vertebrates. In the mid to late 20th century, anatomical variability of early and late-stage embryos and conservation of mid-stages embryos (the "phylotypic" stage) was named the hourglass model of diversification. This model has found mixed support in recent analyses comparing gene expression across species possibly owing to differences in species, embryonic stages, and gene sets compared. We compare 186 microarray and RNA-seq data sets covering embryogenesis in six vertebrate species. We use an unbiased clustering approach to group stages of embryogenesis by transcriptomic similarity and ask whether gene expression similarity of clustered embryonic stages deviates from a null expectation. We characterize expression conservation patterns of each gene at each evolutionary node after correcting for phylogenetic nonindependence. We find significant enrichment of genes exhibiting early conservation, hourglass, late conservation patterns in both microarray and RNA-seq data sets. Enrichment of genes showing patterned conservation through embryogenesis indicates diversification of embryogenesis may be temporally constrained. However, the circumstances under which each pattern emerges remain unknown and require both broad evolutionary sampling and systematic examination of embryogenesis across species.

Smc5/6 in the rDNA modulates lifespan independently of Fob1​.

The ribosomal DNA (rDNA) in Saccharomyces cerevisiae is in one tandem repeat array on Chromosome XII. Two regions within each repetitive element, called intergenic spacer 1 (IGS1) and IGS2, are important for organizing the rDNA within the nucleolus. The Smc5/6 complex localizes to IGS1 and IGS2. We show that Smc5/6 has a function in the rDNA beyond its role in homologous recombination (HR) at the replication fork barrier (RFB) located in IGS1. Fob1 is required for optimal binding of Smc5/6 at IGS1 whereas the canonical silencing factor Sir2 is required for its optimal binding at IGS2, independently of Fob1. Through interdependent interactions, Smc5/6 stabilizes Sir2 and Cohibin at both IGS and its recovery at IGS2 is important for nucleolar compaction and transcriptional silencing, which in turn supports rDNA stability and lifespan.

Kefir peptides exhibit antidepressant-like activity in mice through the BDNF/TrkB pathway.

Depression is a prevalent, stress-related mental disorder that can lead to serious psychiatric diseases with morbidity and high mortality. Although some functional fermented dairy drinks have promising anxiolytic and antidepressant effects, the mechanism is still not clear. To determine the antidepressant-like effect and the potential molecule mechanism of kefir peptides (KP), various behavioral tests, including the elevated plus maze test, open field test, forced swimming test, and tail suspension test, were used. Administration of 150 mg/kg KP in mice reduced the duration of immobility in the forced swimming test and tail suspension test, elevated the time spent in the open arm and center zone in the elevated plus maze test, and increased the total distance traveled, average speed, and time spent in the center zone in the open field test compared with the mock group. These results indicated that KP dramatically ameliorated the depression-like behaviors. Kefir peptides were further isolated and identified using high-performance liquid chromatography and liquid chromatography-tandem mass spectrometry, from which 3 peptides were identified and designated KFP-1, KFP-3, and KFP-5. Among these peptides, administration of KFP-3 (15 AA residues) remarkably decreased immobility time in the forced swimming test and increased mobility time in the tail suspension test. Therefore, KFP-3 may be the major active peptide with antidepressant activity in KP. Overexpression of brain-derived neurotrophic factor, phosphorylated tropomyosin receptor kinase B, and phosphorylated ERK1/2 protein levels could be detected in the hippocampus under KP administration. Therefore, we suggest that KP improves depressive-like behaviors by activating the brain-derived neurotrophic factor-phosphorylated tropomyosin receptor kinase B signaling pathway. Kefir peptides may serve as a new type of antidepressant dairy product and may provide potent antidepressant effects for clinical use.

Gender Differences in Psychological Responses to Recovery After Anterior Cruciate Ligament Reconstruction Before Return to Sport.

CONTEXT: Female patients with anterior cruciate ligament reconstruction (ACLR) are less likely to return to sport than males. Psychological readiness predicts successful return to sport, but it is unclear if psychological experiences differ between males and females during recovery. OBJECTIVE: To explore gender differences in psychological readiness factors of return to sport after ACLR. DESIGN: Qualitative study. SETTING: Laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 12 male (months since surgery = 6.2 ± 1.2) and 13 female (months since surgery = 6.4 ± 1.3) high school athletes with a history of ACLR. DATA COLLECTION AND ANALYSIS: Participants were interviewed before physician clearance to return to activity. Transcribed interviews were analyzed using deductive thematic coding of 5 themes identified from previous research (psychological distress, self-efficacy, locus of control, athletic identity, and fear of reinjury) and inductive secondary subthematic coding. Gender comparisons were generated within primary themes and secondary subthemes. RESULTS: All deductive themes were consistently reinforced. Male and female participants reported fear of movement, loss of athletic identity, and motivational mindsets for return to sport and self-improvement. Males reported a stronger sense of internal locus of control using positive internal reinforcement, whereas females described balancing internal and external control and valuing external support systems. Male participants described mood changes influenced by physical and social limitations. Female participants closely monitored their emotions throughout recovery and were influenced by rehabilitation fluctuations. CONCLUSIONS: Male and female high school athletes described different psychological factors related to return to sport and locus of control as well as psychological distress. Gender-specific psychological interventions may be warranted to overcome psychological barriers after ACLR.

Hair cortisol and dehydroepiandrosterone concentrations: Associations with executive function in early childhood.

Chronic stress during childhood negatively impacts cognition and physical and mental health. Exposure to stressors over time can cause hypothalamic-pituitary-adrenal (HPA) axis dysregulation, leading to abnormal stress hormone levels, which can be reflected in hair cortisol concentration (HCC) and hair dehydroepiandrosterone (DHEA) concentration. Although the use of HCC and DHEA to measure chronic stress in children is increasing, their effects on cognition (as indexed by executive function) remain unexplored. Accordingly, we aimed to investigate the associations of HCC, DHEA, and their ratio with measures of executive function (cognitive flexibility and working memory) in a sample of kindergarten children (N=100). We found that the expected negative association between HCC and working memory approached significance, and DHEA was significantly and positively related to cognitive flexibility. We discuss possible interpretations of our findings. Our results suggest promising areas for future investigation and encourage further exploration into HCC and DHEA as measures of chronic stress.

Changing epidemiology of esophageal stent placement for dysphagia: a decade of trends and the impact of benign indications.

BACKGROUND AND AIMS: In addition to managing malignant obstruction, esophageal stents (ESs) have evolved to address various benign etiologies of dysphagia. We sought to evaluate national trends and changes in practice of ES placement for both benign and malignant etiologies in hospitalized patients with dysphagia. METHODS: The National Inpatient Sample (2003-2013) was used to include all adult inpatients (≥18 years of age) with endoscopy-guided ES placement for a symptom of dysphagia. Multivariable analyses for indications that impact temporal trends (3 time periods: 2003-2005, 2006-2009, and 2010-2013) and for hospital outcomes were performed. RESULTS: A total of 7198 ESs were deployed endoscopically in hospitalized patients with dysphagia. Compared with malignant etiologies, there was a significant increase in ES placement for benign conditions (2013 vs 2003: 32.7% vs 14.5%, respectively; P < .001). Multivariable analysis using 2003 to 2005 as a reference showed that patients with benign etiologies for dysphagia predominantly contributed to the increase of ES placement during the most recent time period (2010-2013: odds ratio, 2.09; 95% confidence interval, 1.40-3.13). Multivariable analysis of hospital outcomes revealed no differences in inpatient mortality, duration of hospital stay, and hospital costs between malignant and benign indications. CONCLUSIONS: In the preceding decade, ES placement for hospitalized patients with dysphagia has increased, driven largely by an over 8-fold rise in stent placement for benign indications. These findings warrant continued efforts to improve stent technology to decrease the risk of migration and review practice guidelines involving ES placement for benign etiologies.

EUS-guided confocal laser endomicroscopy: prediction of dysplasia in intraductal papillary mucinous neoplasms (with video).

BACKGROUND AND AIMS: Previous studies have validated EUS-guided needle-based confocal laser endomicroscopy (nCLE) diagnosis of intraductal papillary mucinous neoplasms (IPMNs). We sought to derive EUS-guided nCLE criteria for differentiating IPMNs with high-grade dysplasia/adenocarcinoma (HGD-Ca) from those with low/intermediate-grade dysplasia (LGD). METHODS: We performed a post hoc analysis of consecutive IPMNs with a definitive diagnosis from a prospective study evaluating EUS-guided nCLE in the diagnosis of pancreatic cysts. Three internal endosonographers reviewed all nCLE videos for the patients and identified potential discriminatory EUS-guided nCLE variables to differentiate HGD-Ca from LGD IPMNs (phase 1). Next, an interobserver agreement (IOA) analysis of variables from phase 1 was performed among 6 blinded external nCLE experts (phase 2). Last, 7 blinded nCLE-naïve observers underwent training and quantified variables with the highest IOA from phase 2 using dedicated software (phase 3). RESULTS: Among 26 IPMNs (HGD-Ca in 16), the reference standard was surgical histopathology in 24 and cytology confirmation of metastatic liver lesions in 2 patients. EUS-guided nCLE characteristics of increased papillary epithelial "width" and "darkness" were the most sensitive variables (90%; 95% confidence interval [CI], 84%-94% and 91%; 95% CI, 85%-95%, respectively) and accurate (85%; 95% CI, 78%-90% and 84%; 95% CI, 77%-89%, respectively) with substantial (κ = 0.61; 95% CI, 0.51-0.71) and moderate (κ = 0.55; 95% CI, 0.45-0.65) IOAs for detecting HGD-Ca, respectively (phase 2). Logistic regression models were fit for the outcome of HGD-Ca as predictor variables (phase 3). For papillary width (cut-off ≥50 µm), the sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) for detection of HGD-Ca were 87.5% (95% CI, 62%-99%), 100% (95% CI, 69%-100%), and 0.95, respectively. For papillary darkness (cut-off ≤90 pixel intensity), the sensitivity, specificity, and AUC for detection of HGD-Ca were 87.5% (95% CI, 62%-99%), 100% (95% CI, 69%-100%), and 0.90, respectively. CONCLUSIONS: In this derivation study, quantification of papillary epithelial width and darkness identified HGD-Ca in IPMNs with high accuracy. These quantifiable variables can be used in multicenter studies for risk stratification of IPMNs. (Clinical trial registration number: NCT02516488.).

Esophageal Dysphagia in the Elderly.

PURPOSE OF REVIEW: With a globally aging population, dysphagia is a growing health concern among elderly. Increasing reflux disease has contributed to an increased prevalence of dysphagia from peptic strictures and esophageal cancer. Dysphagia can lead to malnutrition and aspiration pneumonia, causing considerable morbidity and mortality. This review article focuses on recent advances in the approach and management of esophageal dysphagia. RECENT FINDINGS: Endoscopic functional luminal imaging probe is a novel test that complements upper endoscopy, esophagram, and esophageal manometry for evaluation of esophageal dysphagia. Opioid induced esophageal dysfunction (OIED) is an emerging clinical entity that can mimic achalasia. Strictures refractory to dilation can be treated with intralesional steroid injections, electrosurgical incision, or esophageal stents. Peroral endoscopic myotomy (POEM) is gaining in popularity for treatment of achalasia and other spastic disorders of esophagus. Treatment of esophageal dysphagia may include proton pump inhibitors, endoscopic dilation, or surgery and requires a personalized approach based on risks and benefits. POEM is a valuable therapy for achalasia, but further studies are needed to evaluate its use, and other alternatives, for treatment of OIED and spastic esophageal disorders.

Tropism of influenza B viruses in human respiratory tract explants and airway organoids.

Despite causing regular seasonal epidemics with substantial morbidity, mortality and socioeconomic burden, there is still a lack of research into influenza B viruses (IBVs). In this study, we provide for the first time a systematic investigation on the tropism, replication kinetics and pathogenesis of IBVs in the human respiratory tract.Physiologically relevant ex vivo explant cultures of human bronchus and lung, human airway organoids, and in vitro cultures of differentiated primary human bronchial epithelial cells and type-I-like alveolar epithelial cells were used to study the cellular and tissue tropism, replication competence and induced innate immune response of 16 IBV strains isolated from 1940 to 2012 in comparison with human seasonal influenza A viruses (IAVs), H1N1 and H3N2. IBVs from the diverged Yamagata- and Victoria-like lineages and the earlier undiverged period were included.The majority of IBVs replicated productively in human bronchus and lung with similar competence to seasonal IAVs. IBVs infected a variety of cell types, including ciliated cells, club cells, goblet cells and basal cells, in human airway organoids. Like seasonal IAVs, IBVs are low inducers of pro-inflammatory cytokines and chemokines. Most results suggested a higher preference for the conducting airway than the lower lung and strain-specific rather than lineage-specific pathogenicity of IBVs.Our results highlighted the non-negligible virulence of IBVs which require more attention and further investigation to alleviate the disease burden, especially when treatment options are limited.

Dexrazoxane Significantly Reduces Anthracycline-induced Cardiotoxicity in Pediatric Solid Tumor Patients: A Systematic Review.

Cardiotoxicity is a dose-limiting and potentially lethal complication of anthracycline administration. Previous studies failed to determine definitive toxic doses or cardioprotective factors. Current dosing strategies may utilize unnecessarily high anthracycline doses, such that survival benefit may not outweigh increased toxicity rates. A systematic review of randomized controlled trials and prospective/retrospective studies investigating anthracycline treatment in pediatric solid tumors was performed from PubMed/MEDLINE and Cochrane databases. Generalized linear models mapping survival, cardiotoxicity, and cardiotoxicity-free survival adjusted for male-to-female ratio, follow-up time, and concomitant chemotherapeutic drugs or cardioprotective agents (dexrazoxane) were generated using R. Survival rose linearly with increasing cumulative anthracycline dose whereas cardiotoxicity demonstrated exponential increases both without (dose, >200 mg/m) and with (dose, >400 mg/m) dexrazoxane. Maximum cardiotoxicity-free survival was 268.2 mg/m without and 431.8 mg/m with dexrazoxane. Despite increasing cardiotoxicity-free dose by >150 mg/m, dexrazoxane minimally improved projected survival (71.9% vs. 75.4%). Cardiotoxicity increased linearly as a function of follow-up time with rates doubling from 5 to 20 years, without evidence of plateau. On the basis of our model, current dosing regimens-doxorubicin doses >375 mg/m without dexrazoxane-overvalue increased anthracycline administration and may contribute to devastating cardiotoxicity. The linear increase of cardiotoxicity without evidence of plateau confirms the necessity for lifelong cardiac monitoring.

Near-Infrared 1064 nm Laser Modulates Migratory Dendritic Cells To Augment the Immune Response to Intradermal Influenza Vaccine.

Brief exposure of skin to near-infrared (NIR) laser light has been shown to augment the immune response to intradermal vaccination and thus act as an immunologic adjuvant. Although evidence indicates that the NIR laser adjuvant has the capacity to activate innate subsets including dendritic cells (DCs) in skin as conventional adjuvants do, the precise immunological mechanism by which the NIR laser adjuvant acts is largely unknown. In this study we sought to identify the cellular target of the NIR laser adjuvant by using an established mouse model of intradermal influenza vaccination and examining the alteration of responses resulting from genetic ablation of specific DC populations. We found that a continuous wave (CW) NIR laser adjuvant broadly modulates migratory DC (migDC) populations, specifically increasing and activating the Lang+ and CD11b-Lang- subsets in skin, and that the Ab responses augmented by the CW NIR laser are dependent on DC subsets expressing CCR2 and Langerin. In comparison, a pulsed wave NIR laser adjuvant showed limited effects on the migDC subsets. Our vaccination study demonstrated that the efficacy of the CW NIR laser is significantly better than that of the pulsed wave laser, indicating that the CW NIR laser offers a desirable immunostimulatory microenvironment for migDCs. These results demonstrate the unique ability of the NIR laser adjuvant to selectively target specific migDC populations in skin depending on its parameters, and highlight the importance of optimization of laser parameters for desirable immune protection induced by an NIR laser-adjuvanted vaccine.

Semiconductor diode laser device adjuvanting intradermal vaccine.

A brief exposure of skin to a low-power, non-tissue damaging laser light has been demonstrated to augment immune responses to intradermal vaccination. Both preclinical and clinical studies show that this approach is simple, effective, safe and well tolerated compared to standard chemical or biological adjuvants. Until now, these laser exposures have been performed using a diode-pumped solid-state laser (DPSSL) devices, which are expensive and require labor-intensive maintenance and special training. Development of an inexpensive, easy-to-use and small device would form an important step in translating this technology toward clinical application. Here we report that we have established a handheld, near-infrared (NIR) laser device using semiconductor diodes emitting either 1061, 1258, or 1301nm light that costs less than $4000, and that this device replicates the adjuvant effect of a DPSSL system in a mouse model of influenza vaccination. Our results also indicate that a broader range of NIR laser wavelengths possess the ability to enhance vaccine immune responses, allowing engineering options for the device design. This small, low-cost device establishes the feasibility of using a laser adjuvant approach for mass-vaccination programs in a clinical setting, opens the door for broader testing of this technology with a variety of vaccines and forms the foundation for development of devices ready for use in the clinic.

Innate immune interleukin-1 receptor-associated kinase 4 exacerbates viral myocarditis by reducing CCR5(+) CD11b(+) monocyte migration and impairing interferon production.

BACKGROUND: Viral myocarditis follows a fatal course in ≈30% of patients. Interleukin-1 receptor-associated kinase 4 (IRAK4), a major nodal signal transducer in innate immunity, can play a pivotal role in host inflammatory response. We sought to determine how IRAK4 modulates inflammation and outcome in a mouse model of viral myocarditis. METHODS AND RESULTS: Myocarditis was induced after intraperitoneal inoculation of coxsackievirus B3 into C57Bl/6 IRAK4-deficient mice and their littermate controls. Mortality and viral proliferation were markedly reduced in IRAK4(-/-) mice compared with their IRAK4(+/+) littermates. Disease resistance of IRAK4(-/-) mice paralleled increased amounts of protective heart-infiltrating CCR5(+) monocytes/macrophages and enhanced interferon-α and interferon-γ production 2 days after infection. Competitive bone marrow chimera demonstrated that intact IRAK4 function inhibited heart-specific migration of bone marrow-derived CCR5(+) cells. Mechanistically, lack of IRAK4 resulted in interferon regulatory factor 5 homodimerization via reduced melanoma differentiation-associated protein 5 degradation and enhanced Stat1 and Stat5 phosphorylation. Consequently, antiviral interferon-α and interferon-γ production, as well as CCR5(+) cell recruitment, increased, whereas the overall proinflammatory response was drastically reduced in the absence of IRAK4. CONCLUSIONS: Innate immunity signal transducer IRAK4 exacerbates viral myocarditis through inhibition of interferon production and reduced mobilization of protective CCR5(+) monocytes/macrophages to the heart. The combination of IRAK4 inhibitors and antiviral adjuvants may become an attractive therapeutic approach against viral myocarditis in the future.

IL-12p70-producing patient DC vaccine elicits Tc1-polarized immunity.

BACKGROUND: Systemic administration of IL-12p70 has demonstrated clinical activity in cancer patients, but dose-limiting toxicities have hindered its incorporation in vaccine formulations. Here, we report on the immunological and clinical outcomes upon vaccination with CD40L/IFN-γ-matured, IL-12p70-producing DCs. METHODS: 7 HLA-A*0201+ newly diagnosed stage IV melanoma patients were immunized against the gp100 melanoma antigen using autologous peptide-pulsed, CD40L/IFN-γ-matured DCs. PBMCs were taken weekly for immune monitoring by tetramer analysis and functional assays. CT imaging was performed at baseline, week 9, and week 18 for clinical assessment using RECIST. RESULTS: 6 of 7 treated patients developed sustained T cell immunity to all 3 melanoma gp100 antigen-derived peptides. 3 of the 6 immunological responders developed confirmed clinical responses (1 complete remission >4 years, 2 partial response). Importantly, DC vaccine-derived IL-12p70 levels positively correlated with time to progression (P = 0.019, log-rank), as did T-cytotoxic 1 (Tc1) immunity, as assessed by IFN-γ/IL-13 and IFN-γ/IL-5 ratios (P = 0.035 and P = 0.030, respectively, log-rank). In contrast, a pathway-specific defect in IL-12p35 transcription was identified upon CD40L/IFN-γ activation in clinical nonresponder patient DCs, and gp100-specific T cells from these patients displayed a Tc2 phenotype. Incorporation of TLR3 and TLR8 agonists into the CD40L/IFN-γ activation protocol corrected the IL-12p70 production defect in DCs derived from clinical nonresponder patients. CONCLUSION: These findings underscore the essential role of IL-12p70 in the development of therapeutic type 1 antigen-specific CD8+ T cell immunity in humans with cancer.