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Abstract Background During an influenza pandemic, a substantial proportion of transmission is thought to occur in households. We used data on influenza progression in individuals and their contacts collected by the City of Milwaukee Health Department (MHD) to study the transmission of pandemic influenza A/H1N1 virus in 362 households in Milwaukee, WI, and the effects of oseltamivir treatment and chemoprophylaxis. Methods 135 households had chronological information on symptoms and oseltamivir usage for all household members. The effect of oseltamivir treatment and other factors on the household secondary attack rate was estimated using univariate and multivariate logistic regression with households as the unit of analysis. The effect of oseltamivir treatment and other factors on the individual secondary attack rate was estimated using univariate and multivariate logistic regression with individual household contacts as the unit of analysis, and a generalized estimating equations approach was used to fit the model to allow for clustering within households. Results Oseltamivir index treatment on onset day or the following day (early treatment) was associated with a 42% reduction (OR: 0.58, 95% CI: 0.19, 1.73) in the odds of one or more secondary infections in a household and a 50% reduction (OR: 0.5, 95% CI: 0.17, 1.46) in the odds of a secondary infection in individual contacts. The confidence bounds are wide due to a small sample of households with early oseltamivir index usage - in 29 such households, 5 had a secondary attack. Younger household contacts were at higher risk of infection (OR: 2.79, 95% CI: 1.50-5.20). Conclusions Early oseltamivir treatment may be beneficial in preventing H1N1pdm influenza transmission; this may have relevance to future control measures for influenza pandemics. Larger randomized trials are needed to confirm this finding statistically.

Abstract Background After the WHO issued the global alert for 2009 pandemic influenza A (H1N1), many national health agencies began to screen travelers on entry in airports, ports and border crossings to try to delay local transmission. Methods We reviewed entry screening policies adopted by different nations and ascertained dates of official report of the first laboratory-confirmed imported H1N1 case and the first laboratory-confirmed untraceable or 'local' H1N1 case. Results Implementation of entry screening policies was associated with on average additional 7-12 day delays in local transmission compared to nations that did not implement entry screening, with lower bounds of 95% confidence intervals consistent with no additional delays and upper bounds extending to 20-30 day additional delays. Conclusions Entry screening may lead to short-term delays in local transmission of a novel strain of influenza virus. The resources required for implementation should be balanced against the expected benefits of entry screening.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has shown wastewater (WW) surveillance to be an effective means of tracking the emergence of viral lineages which arrive by many routes of transmission including via transportation hubs. In the Canadian province of Ontario, numerous municipal wastewater treatment plants (WWTPs) participate in WW surveillance of infectious disease targets such as SARS-CoV-2 by qPCR and whole genome sequencing (WGS). The Greater Toronto Airports Authority (GTAA), operator of Toronto Pearson International Airport (Toronto Pearson), has been participating in WW surveillance since January 2022. As a major international airport in Canada and the largest national hub, this airport is an ideal location for tracking globally emerging SARS-CoV-2 variants of concern (VOCs). In this study, WW collected from Toronto Pearson's two terminals and pooled aircraft sewage was processed for WGS using a tiled-amplicon approach targeting the SARS-CoV-2 virus genome. Data generated was analyzed to monitor trends of SARS-CoV-2 lineage frequencies. Initial detections of emerging lineages were compared between Toronto Pearson WW samples, municipal WW samples collected from the surrounding regions, and Ontario clinical data as published by Public Health Ontario. Results enabled the early detection of VOCs and individual mutations emerging in Ontario. On average, the emergence of novel lineages at the airport preceded clinical detections by 1-4 weeks, and up to 16 weeks in one case. This project illustrates the efficacy of WW surveillance at transitory transportation hubs and sets an example that could be applied to other viruses as part of a pandemic preparedness strategy and to provide monitoring on a mass scale., (© 2024. The Author(s).)

Introduction: Despite the benefits of intramedullary nailing (IMN) of impending or pathologic fractures in oncologic patients, literature on patient-reported outcomes (PROs) is scarce in patients treated with carbon fiber (CF) nails. Our study compared postoperative PROs after IMN with CF or titanium implants., Methods: We conducted a retrospective propensity score-matched cohort study of patients treated at our institution with CF or titanium nails for impending or pathologic fractures from metastatic bone disease. Patient-Reported Outcomes Measurement Information System (PROMIS) Global Health Short Form (SF) Physical, Mental, and Physical Function 10a scores were collected. Pain was assessed using visual analog scale (VAS). Absolute and differential scores were compared between groups., Results: We included 207 patients, 51 treated with CF and 156 with titanium nails. One month postoperatively, patients had a one-point decrease in the pain VAS score while PROMIS scores did not improve. At 3 months, PROMIS SF Physical and SF 10a scores improved from preoperative values. Six months postoperatively, median PROMIS SF Physical, SF Mental, and SF 10a scores were higher than preoperative scores. Absolute and differential PROMIS and pain VAS scores were similar between groups at the 6-month and 1-year marks., Conclusion: Patient-reported outcomes were similar after intramedullary nailing with either CF or titanium implants., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Orthopaedic Surgeons.)

Background: Implementation strategies are strategies to improve uptake of evidence-based practices or interventions and are essential to implementation science. Developing or tailoring implementation strategies may benefit from integrating approaches from other disciplines; yet current guidance on how to effectively incorporate methods from other disciplines to develop and refine innovative implementation strategies is limited. We describe an approach that combines community-engaged methods, human-centered design (HCD) methods, and causal pathway diagramming (CPD)-an implementation science tool to map an implementation strategy as it is intended to work-to develop innovative implementation strategies., Methods: We use a case example of developing a conversational agent or chatbot to address racial inequities in breast cancer screening via mammography. With an interdisciplinary team including community members and operational leaders, we conducted a rapid evidence review and elicited qualitative data through interviews and focus groups using HCD methods to identify and prioritize key determinants (facilitators and barriers) of the evidence-based intervention (breast cancer screening) and the implementation strategy (chatbot). We developed a CPD using key determinants and proposed strategy mechanisms and proximal outcomes based in conceptual frameworks., Results: We identified key determinants for breast cancer screening and for the chatbot implementation strategy. Mistrust was a key barrier to both completing breast cancer screening and using the chatbot. We focused design for the initial chatbot interaction to engender trust and developed a CPD to guide chatbot development. We used the persuasive health message framework and conceptual frameworks about trust from marketing and artificial intelligence disciplines. We developed a CPD for the initial interaction with the chatbot with engagement as a mechanism to use and trust as a proximal outcome leading to further engagement with the chatbot., Conclusions: The use of interdisciplinary methods is core to implementation science. HCD is a particularly synergistic discipline with multiple existing applications of HCD to implementation research. We present an extension of this work and an example of the potential value in an integrated community-engaged approach of HCD and implementation science researchers and methods to combine strengths of both disciplines and develop human-centered implementation strategies rooted in causal perspective and healthcare equity., (© 2024. The Author(s).)

Introduction: The effectiveness of mailed fecal immunochemical test outreach might be enhanced through an organized colorectal cancer screening program, yet published real-world experiences are limited. We synthesized the process of implementing a colorectal cancer screening program that used mailed fecal immunochemical test outreach in a large integrated academic-community practice., Methods: Data from a pilot mailed fecal immunochemical test program were shared with healthcare system leadership, which inspired the creation of a cross-institutional organized colorectal cancer screening program. In partnership with a centralized population health team and primary care, we defined (1) the institutional approach to colorectal cancer screening, (2) the target population and method for screening, (3) the team responsible for implementation, (4) the healthcare team responsible for decisions and care, (5) a quality assurance structure, and (6) a method for identifying cancer occurrence., Results: The Fred Hutch/UW Medicine Population Health Colorectal Cancer Screening Program began in September 2021. The workflow for mailed fecal immunochemical test outreach included a mailed postcard, a MyChart message from the patient's primary care provider, a fecal immunochemical test kit with a letter signed by the primary care provider and program director, and up to 3 biweekly reminders. Patients without a colonoscopy 3 months after an abnormal fecal immunochemical test result received navigation through the program. In the first program year, we identified 9,719 patients eligible for outreach, and in an intention-to-treat analysis, 32% of patients completed colorectal cancer screening by fecal immunochemical test or colonoscopy., Conclusions: Real-world experiences detailing how to implement organized colorectal cancer screening programs might increase adoption. In our experience, broadly disseminating pilot data, early institutional support, robust data management, and strong cross-departmental relationships were critical to successfully implementing a colorectal cancer screening program that benefits all patients., (© 2024 The Authors.)

Background: The prolonged air leak is probably the most common complication following lung resections. Around 10-20% of the patients who undergo a lung resection will eventually develop a prolonged air leak. The definition of a prolonged air leak varies between an air leak, which is evident after the fifth, seventh or even tenth postoperative day to every air leak that prolongs the hospital stay. However, the postoperative hospital stay following a thoracoscopic lobectomy can be as short as 2 days, making the above definitions sound outdated. The treatment of these air leaks is also very versatile. One of the broadly accepted treatment options is the autologous blood pleurodesis or "blood patch". The purpose of this trial is to investigate the impact of a prophylactic autologous blood pleurodesis on reducing the duration of the postoperative air leak and therefore prevent the air leak from becoming prolonged., Methods: Patients undergoing an elective thoracoscopic anatomic lung resection for primary lung cancer or metastatic disease will be eligible for recruitment. Patients with an air leak of > 100 ml/min within 6 h prior to the morning round on the second postoperative day will be eligible for inclusion in the study and randomization. Patients will be randomized to either blood pleurodesis or watchful waiting. The primary endpoint is the time to drain removal measured in full days. The trial ends on the seventh postoperative day., Discussion: The early autologous blood pleurodesis could lead to a faster cessation of the air leak and therefore to a faster removal of the drain. A faster removal of the drain would relieve the patient from all the well-known drain-associated complications (longer hospital stay, stronger postoperative pain, risk of drain-associated infection, etc.). From the economical point of view, faster drain removal would reduce the hospital costs as well as the costs associated with the care of a patient with a chest drain in an outpatient setting., Trial Registration: German Clinical Trials Register (DRKS) DRKS00030810. 27 December 2022., (© 2023. The Author(s).)

The impacts of hydraulic fracturing (HF) on birth defects have been suggested by previous studies but remain largely inconclusive. In this study, we assessed whether pregnant women who lived in areas with high HF activities had increased risks of giving birth to offspring with overall or specific birth defects, including atrial septal defect (ASD), ventricular septal defect (VSD), patent ductus arteriosus (PDA), microcephaly (MIC), and hydrocephaly without spina bifida (HSB). All live births between 1999 and 2014 among the residents in the four core counties of Denton, Johnson, Tarrant, and Wise in the Barnett Shale region, Texas, were analyzed. Standardized Morbidity Ratio (SMR) and Poisson regressions were applied for statistical analysis. Compared to the statewide risk, the risks of ASD, VSD, and PDA in four selected counties with high HF activities were significantly higher. The Annual Natural Gas Production from HF was significantly correlated with risks of ASD, PDA, MIC, and total birth defect after adjusting for counties and years. No significant associations of HF activities were found with VSD and HSB. This ecological study suggested that hydraulic fracturing might be associated with the increased risk of some birth defects in the Barnett Shale Region, TX, which warrants further investigations due to the limitation of an ecological study design., (© 2023 The Authors.)

Inflammation is the body's response to injury and harmful stimuli and contributes to a range of infectious and noninfectious diseases. Inflammation occurs through a series of well-defined leukocyte-endothelial cell interactions, including rolling, activation, adhesion, transmigration, and subsequent migration through the extracellular matrix. Being able to visualize the stages of inflammation is important for a better understanding of its role in diseases processes. Detailed in this article are protocols for imaging immune cell infiltration and transendothelial migration in vascular tissue beds, including those in the mouse ear, cremaster muscle, brain, lung, and retina. Also described are protocols for inducing inflammation and quantifying leukocytes with FIJI imaging software. © 2023 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Induction of croton oil dermatitis Alternate Protocol 1: Induction of croton oil dermatitis using genetically fluorescent mice Basic Protocol 2: Intravital microscopy of the mouse cremaster muscle Support Protocol: Making a silicone stage Basic Protocol 3: Wide-field microscopy of the mouse brain Basic Protocol 4: Imaging the lungs (ex vivo) Alternate Protocol 2: Inflating the lungs without tracheostomy Basic Protocol 5: Inducing, imaging, and quantifying infiltration of leukocytes in mouse retina., (© 2023 The Authors. Current Protocols published by Wiley Periodicals LLC.)

Competing Interests: Dr Rosenbach is a member of the American Academy of Dermatology’s COVID-19 Ad Hoc Task Force. Drs Mintz, Jariwala, Fang, and Coromilas have no conflicts of interest to declare.

Purpose: To evaluate visual function (VF) changes in early and intermediate age-related macular degeneration (eAMD and iAMD) over 24 months., Design: Prospective, observational natural history study., Participants: Participants were enrolled at the Duke Eye Center., Methods: A total of 101 subjects (33 with eAMD, 47 with iAMD, and 21 normal controls) were recruited. Visual function (VF) tests included best-corrected visual acuity (BCVA), low- luminance visual acuity (LLVA), microperimetry (MP), cone contrast tests (CCTs), and dark adaptation (DA). Mixed-effect model repeated measures based on absolute values and change from baseline identified VF tests differentiating AMD from controls and revealing longitudinal VF decline when controlling for covariates (baseline value, age, coronary artery disease, dry eye, and phakic status). Nine AMD genetic risk variants, combinations of these (genetic burden score), reticular pseudodrusen (RPD), and hyperreflective foci (HRF) were tested as predictors of diagnosis and VF performance., Main Outcome Measures: Longitudinal changes in VF metrics over 24 months., Results: A total of 70 subjects completed the 2-year visit (22 with eAMD, 31 with iAMD, and 17 controls). Percent reduced threshold (PRT) on MP and CCT red significantly distinguished iAMD versus controls after 12 and 24 months, respectively. Cone contrast test red, PRT, and absolute threshold (AT) on MP showed significant longitudinal deterioration of VF in iAMD versus baseline at 12 months and onward, however, with a reduced rate of worsening. The DA data confirmed a preexisting functional deficit in iAMD at baseline and revealed an increasing proportion of poorly performing iAMD subjects in DA over the study period. None of the other VF measures showed consistent significant changes among the normal, early, and intermediate groups or over time. The genetic burden score was significantly associated with AMD diagnosis (relative risk for iAMD = 1.64, P  < 0.01) and DA ( r  = 0.42, P  = 0.00005). Reticular pseudodrusen and HRF showed moderate associations with DA and weak to moderate associations with MP variables., Conclusions: In iAMD, MP variables, CCT red, and DA revealed slow and nonlinear functional decline over 24 months. A structure-function relationship in eAMD and iAMD stages was demonstrated among HRF, RPD, and DA, possibly modified by genetic risk factors. These structural and functional features represent potential end points for clinical trials in iAMD., (© 2022 by the American Academy of Ophthalmology.)

Background & Aims: The incidence of inflammatory bowel disease (IBD) is increasing internationally, particularly in nations with historically low rates. Previous reports of the epidemiology of pediatric-onset IBD identified a paucity of data. We systematically reviewed the global trends in incidence and prevalence of IBD diagnosed in individuals <21 years old over the first 2 decades of the 21st century., Methods: We systematically reviewed studies indexed in MEDLINE, EMBASE, Airiti Library, and SciELO from January 2010 to February 2020 to identify population-based studies reporting the incidence and/or prevalence of IBD, Crohn's disease, ulcerative colitis, and/or IBD-unclassified. Data from studies published before 2000 were derived from a previously published systematic review. We described the geographic distribution and trends in children of all ages and limiting to very early onset (VEO) IBD., Results: A total of 131 studies from 48 countries were included. The incidence and prevalence of pediatric-onset IBD is highest in Northern Europe and North America and lowest in Southern Europe, Asia, and the Middle East. Among studies evaluating trends over time, most (31 of 37, 84%) studies reported significant increases in incidence and all (7 of 7) reported significant increases in prevalence. Data on the incidence and prevalence of VEO-IBD are limited to countries with historically high rates of IBD. Time trends in the incidence of VEO-IBD were visually heterogeneous., Conclusions: Rates of pediatric-onset IBD continue to rise around the world and data are emerging from regions where it was not previously reported; however, there remains a paucity of data on VEO-IBD and on pediatric IBD from developing and recently developed countries., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

T cell expression of sphingosine 1-phosphate (S1P) receptor 1 (S1PR1) enables T cell exit from lymph nodes (LNs) into lymph, while endothelial S1PR1 expression regulates vascular permeability. Drugs targeting S1PR1 treat autoimmune disease by trapping pathogenic T cells within LNs, but they have adverse cardiovascular side effects. In homeostasis, the transporter SPNS2 supplies lymph S1P and enables T cell exit, while the transporter MFSD2B supplies most blood S1P and supports vascular function. It is unknown whether SPNS2 remains necessary to supply lymph S1P during an immune response, or whether in inflammation other compensatory transporters are upregulated. Here, using a model of dermal inflammation, we demonstrate that SPNS2 supplies the S1P that guides T cells out of LNs with an ongoing immune response. Furthermore, deletion of Spns2 is protective in a mouse model of multiple sclerosis. These results support the therapeutic potential of SPNS2 inhibitors to achieve spatially specific modulation of S1P signaling., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Benign tracheal stenosis is a life-threatening condition that needs a prompt treatment when the tracheal lumen is less than 5 mm. In patients unfit for surgery, endoscopic dilation with stent insertion (if indicated) remains the main alternative to restore airway patency and assure ventilation. Endoscopic management of tracheal stenosis may be a cumbersome procedure, that sometimes takes a long time, and may be complicated by stent dislocation especially in cases of complex stenosis, near to vocal folds. In recent years, the 3D printing industry has undergone rapid development, and 3D printing model has been increasingly applied to different medical fields where therapeutic interventions rely on defining complex anatomic structural relationships. Thus, in this review we aimed to evaluate whether the use of 3D printing model as tool for preoperative planning could facilitate the endoscopic treatment of tracheal stenosis and improve outcome. Three papers evaluated this issue: one paper reported a consecutive series of patients while the remaining single case report. All authors concluded that the 3D model aided the understanding of patient's anatomy and the stenosis's characteristic. The possibility of recreating the endoscopic procedure in the 3D model facilitated and shorted the procedural time in live patient. Furthermore, the 3D model was additionally useful to choose the length, diameter and shape of stent and to define the exact distance of the proximal end of stent from the vocal folds after its insertion. Finally, it represented an educational tool for patients and his/her family to understand the procedure, and for residents and fellows to improve endoscopic skills., Competing Interests: Conflicts of Interest: All authors have completed the ICJME disclosure form (available at http://dx.doi.org/10.21037/tcr.2020.01.22). The series “Recent Developments in Benign Tracheal Stenosis” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare., (2020 Translational Cancer Research. All rights reserved.)

Objective: To characterize coping and distress among parents of children with retinoblastoma, and to uncover their association with perceived health literacy, self-efficacy, and social support., Methods: This was a cross-sectional study performed in the retinoblastoma clinics of Beijing Children's Hospital, Jilin Eye Hospital and Changchun Hospital in China. Parents of children with retinoblastoma (n = 104) completed a print Mandarin language questionnaire consisting of four sections: (i) demographic information, (ii) mini-mental adjustment to cancer scale, (iii) hospital anxiety and depression scale, and (iv) perceived health literacy, self-efficacy, and social support scales. Scores were tabulated for each measure and analyzed by bivariate correlation., Results: Moderate anxiety affected 59.2% of parents, and 77.7% experienced low, moderate, or high levels of depression. Combined anxiety and depression was positively correlated with helplessness/hopelessness (R = 0.42, p < .01) and anxious preoccupation (R = 0.247, p < .05), and negatively correlated with perceived self-efficacy (R = -0.228, p < .05). Perceived social support from a partner was negatively correlated with depression (R = -0.207, p < .05) and helplessness/hopelessness (R = -0.271, p < .01)., Conclusions: Knowledge of how parents cope with their child's cancer diagnosis can help healthcare teams understand how best to support their psychosocial needs.

Background: Despite evidence that biological and genetic factors contribute strongly to obesity, many healthcare providers still attribute obesity more to controllable behavioral issues rather than factors outside a person's control. We evaluated whether medical school students' beliefs about obesity correlate with ability to effectively counsel patients with obesity., Methods: Clerkship-year medical students at NYU School of Medicine completed an Objective Structured Clinical Experience (OSCE) that tests ability to effectively counsel standardized actor-patients with obesity. We surveyed these students to evaluate their beliefs about the causes of obesity and their attitudes towards people with obesity. We analyzed correlations between student beliefs, negative obesity attitudes, and OSCE performance., Results: The response rate was 60.7% ( n  = 71). When asked to rate the importance of individual factors, students rated controllable factors such as unhealthy diet, physical inactivity, and overeating as more important than genetics or biological factors ( p  < 0.01). Believing obesity is caused by uncontrollable factors was negatively correlated with obesity bias ( r  = - 0.447; p  < 0.0001). Believing that obesity is caused by factors within a person's control was negatively correlated with counseling skills ( r  = - 0.235; p  < 0.05)., Conclusions: Attribution of obesity to external factors correlated with greater ability to counsel patients with obesity, suggesting that educating providers on the biological causes of obesity could help reduce bias and improve provider care., Competing Interests: Students had provided written consent for their routinely collected educational data to be used for medical education research as part of an NYU IRB-approved medical student research registry.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Balancer chromosomes are multiply inverted and rearranged chromosomes used in Drosophila melanogaster for many tasks, such as maintaining mutant alleles in stock and complex stock construction. Balancers were created before molecular characterization of their breakpoints was possible, so the precise locations of many of these breakpoints are unknown. Here, we report or confirm the positions of the 14 euchromatic breakpoints on the 2 nd chromosome balancers SM1 , SM5 , CyO , and SM6a This total includes three breakpoints involved in a complex rearrangement on SM5 that is associated with the duplication of two genomic regions. Unbiased sequencing of several balancers allowed us to identify stocks with incorrectly identified balancers as well as single and double crossover events that had occurred between 2 nd chromosome balancers and their homologs. The confirmed crossover events that we recovered were at least 2 Mb from the closest inversion breakpoint, consistent with observations from other balancer chromosomes. Balancer chromosomes differ from one another both by large tracts of sequence diversity generated by recombination and by small differences, such as single nucleotide polymorphisms (SNPs). Therefore, we also report loss-of-function mutations carried by these chromosomes and unique SNP and InDel polymorphisms present on only single balancers. These findings provide valuable information about the structure of commonly used 2 nd chromosome balancers and extend recent work examining the structure of X and 3 rd chromosome balancers. Finally, these observations provide new insights into how the sequences of individual balancers have diverged over time., (Copyright © 2018 Miller et al.)

Peri-implantitis remains one of the most challenging complications that could threaten the long-term survival of implants. The aim of this survey is to explore the experiences, attitudes and challenges that face clinicians in the management of peri-implantitis. A validated online questionnaire was emailed to implant clinicians in the United Kingdom. 72 clinicians responded to the questionnaire, all of whom face many challenges during the treatment of peri-implantitis, with 79% finding difficulties due to lack of treatment consensus and 78% finding treatment outcomes unpredictable. This survey highlights the marked differences in opinion and attitudes of clinicians in the management of peri-implantitis., (Copyright© 2018 Dennis Barber Ltd.)

Effective adaptive immune responses require a large repertoire of naive T cells that migrate throughout the body, rapidly identifying almost any foreign peptide. Because the production of T cells declines with age, naive T cells must be long-lived. However, it remains unclear how naive T cells survive for years while constantly travelling. The chemoattractant sphingosine 1-phosphate (S1P) guides T cell circulation among secondary lymphoid organs, including spleen, lymph nodes and Peyer's patches, where T cells search for antigens. The concentration of S1P is higher in circulatory fluids than in lymphoid organs, and the S1P 1 receptor (S1P 1 R) directs the exit of T cells from the spleen into blood, and from lymph nodes and Peyer's patches into lymph. Here we show that S1P is essential not only for the circulation of naive T cells, but also for their survival. Using transgenic mouse models, we demonstrate that lymphatic endothelial cells support the survival of T cells by secreting S1P via the transporter SPNS2, that this S1P signals through S1P 1 R on T cells, and that the requirement for S1P 1 R is independent of the established role of the receptor in guiding exit from lymph nodes. S1P signalling maintains the mitochondrial content of naive T cells, providing cells with the energy to continue their constant migration. The S1P signalling pathway is being targeted therapeutically to inhibit autoreactive T cell trafficking, and these findings suggest that it may be possible simultaneously to target autoreactive or malignant cell survival.

The lymph node periphery is an important site for many immunological functions, from pathogen containment to the differentiation of helper T cells, yet the cues that position cells in this region are largely undefined. Here, through the use of a reporter for the signaling lipid S1P (sphingosine 1-phosphate), we found that cells sensed higher concentrations of S1P in the medullary cords than in the T cell zone and that the S1P transporter SPNS2 on lymphatic endothelial cells generated this gradient. Natural killer (NK) cells are located at the periphery of the lymph node, predominantly in the medulla, and we found that expression of SPNS2, expression of the S1P receptor S1PR5 on NK cells, and expression of the chemokine receptor CXCR4 were all required for NK cell localization during homeostasis and rapid production of interferon-γ by NK cells after challenge. Our findings elucidate the spatial cues for NK cell organization and reveal a previously unknown role for S1P in positioning cells within the medulla.

CD8(+) T cells develop increased sensitivity following Ag experience, and differences in sensitivity exist between T cell memory subsets. How differential TCR signaling between memory subsets contributes to sensitivity differences is unclear. We show in mouse effector memory T cells (TEM) that >50% of lymphocyte-specific protein tyrosine kinase (Lck) exists in a constitutively active conformation, compared with <20% in central memory T cells (TCM). Immediately proximal to Lck signaling, we observed enhanced Zap-70 phosphorylation in TEM following TCR ligation compared with TCM Furthermore, we observed superior cytotoxic effector function in TEM compared with TCM, and we provide evidence that this results from a lower probability of TCM reaching threshold signaling owing to the decreased magnitude of TCR-proximal signaling. We provide evidence that the differences in Lck constitutive activity between CD8(+) TCM and TEM are due to differential regulation by SH2 domain-containing phosphatase-1 (Shp-1) and C-terminal Src kinase, and we use modeling of early TCR signaling to reveal the significance of these differences. We show that inhibition of Shp-1 results in increased constitutive Lck activity in TCM to levels similar to TEM, as well as increased cytotoxic effector function in TCM Collectively, this work demonstrates a role for constitutive Lck activity in controlling Ag sensitivity, and it suggests that differential activities of TCR-proximal signaling components may contribute to establishing the divergent effector properties of TCM and TEM. This work also identifies Shp-1 as a potential target to improve the cytotoxic effector functions of TCM for adoptive cell therapy applications., (Copyright © 2016 by The American Association of Immunologists, Inc.)

Whereas the role of sphingosine 1-phosphate receptor 1 (S1PR1) in T cell egress and the regulation of S1P gradients between lymphoid organs and circulatory fluids in homeostasis are increasingly well understood, much remains to be learned about S1P signaling and distribution during an immune response. Recent data suggest that the role of S1PR1 in directing cells from tissues into circulatory fluids is reprised again and again, particularly in guiding activated T cells from non-lymphoid tissues into lymphatics. Conversely, S1P receptor 2 (S1PR2), which antagonizes migration towards chemokines, confines cells within tissues. Here we review the current understanding of the roles of S1P signaling in activated T cell migration. In this context, we outline open questions, particularly regarding the shape of S1P gradients in different tissues in homeostasis and inflammation, and discuss recent strategies to measure S1P., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Despite the importance of signaling lipids, many questions remain about their function because few tools are available for charting lipid gradients in vivo. Here we generated a sphingosine 1-phosphate (S1P) reporter mouse and used this mouse to define the distribution of S1P in the spleen. Unexpectedly, the presence of blood did not serve as a predictor of the concentration of signaling-available S1P. Large areas of the red pulp had low concentrations of S1P, while S1P was sensed by cells inside the white pulp near the marginal sinus. The lipid phosphate phosphatase LPP3 maintained low S1P concentrations in the spleen and enabled efficient shuttling of marginal zone B cells. The exquisitely tight regulation of S1P availability might explain how a single lipid can simultaneously orchestrate the movements of many cells of the immune system.

Respiratory viruses cause acute respiratory diseases with a broad and overlapping spectrum of symptoms. We examined the clinical symptoms and explored the patterns of various respiratory viral infections in children in Hong Kong. Among 2090 specimens collected from outpatient care (2007-2010), 1343 (64.3%) were positive for any virus by the xTAG assay, and 81 (3.9%) were positive for co-infection. The most frequently detected viruses among children aged 6-15 years were enterovirus/rhinovirus and influenza virus A, whereas most non-influenza viruses were more frequently detected in younger children. Higher body temperature was more common for illnesses associated with influenza viruses than for those associated with non-influenza viruses, but other symptoms were largely similar across all infections. The seasonality pattern varied among different viruses, with influenza virus A being the predominant virus detected in winter, and enterovirus/rhinovirus being more commonly detected than influenza virus A in the other three seasons, except for 2009., (Copyright © 2015 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

The contributions of TGF-β signaling to cancer are complex but involve the inflammatory microenvironment as well as cancer cells themselves. In mice encoding a TGF-β mutant that precludes its binding to the latent TGF-β binding protein (Tgfb1(-/C33S)), we observed multiorgan inflammation and an elevated incidence of various types of gastrointestinal solid tumors due to impaired conversion of latent to active TGF-β1. By genetically eliminating activators of latent TGF-β1, we further lowered the amount of TGF-β, which enhanced tumor frequency and multiorgan inflammation. This model system was used to further investigate the relative contribution of TGF-β1 to lymphocyte-mediated inflammation in gastrointestinal tumorigenesis. Toward this end, we generated Tgfb1(-/C33S);Rag2(-/-) mice that lacked adaptive immune function, which eliminated tumor production. Analysis of tissue from Tgfb1(-/C33S) mice indicated decreased levels of P-Smad3 compared with wild-type animals, whereas tissue from Tgfb1(-/C33S);Rag2(-/-) mice had normal P-Smad3 levels. Inhibiting the inflammatory response normalized levels of interleukin (IL)-1β and IL-6 and reduced tumor cell proliferation. In addition, Tgfb1(-/C33S);Rag2(-/-) mice exhibited reduced paracrine signaling in the epithelia, mediated by hepatocyte growth factor produced by gastric stroma. Together, our results indicate that many of the responses of the gastric tissue associated with decreased TGF-β1 may be directly or indirectly affected by inflammatory processes, which accompany loss of TGF-β1, rather than a direct effect of loss of the cytokine., (©2014 AACR.)

Resistin, the peptide specifically secreted from adipocytes, is a hormone antagonistic to insulin action and, thus, may serve as a link between human obesity due to adiposity and insulin resistance associated with type 2 diabetes. To test this hypothesis, we studied the gene expression of resistin in adipocytes isolated from rats fed with a fructose diet which induced insulin resistance. Compared to the control rats (C) on a normal chow diet, the fructose-fed rats (F) developed hyperinsulinemia, glucose intolerance, hypertriglyceridemia and hypertension, a profile reminiscent of the syndrome X of patients with non-insulin-dependent diabetes mellitus (NIDDM). The F rats had significantly elevated plasma free fatty acids (FFA), enlarged epididymal fat pads, and increased adipocyte size compared with the C rats. We examined the glucose transport and the relative quantity of resistin mRNA produced in the adipocytes of these two groups of rats. Compared to the C rats, the F rats had a clearly reduced insulin-stimulated glucose transport. The gene expression of resistin and other adipocyte peptides was measured on the mRNA by semiquantitative RT-PCR; the validity of this technique was established in advance with a rat-fasting and then refeeding experiment. The F rats showed a decreased expression of the resistin gene, whereas gene expression of leptin and angiotensinogen in contrast increased. Free fatty acids were found to suppress the expression of resistin gene in normal rat adipocytes. These results demonstrate that an insulin-resistant instance in the fructose diet rat model exists with the decreased gene expression of resistin.