Individuals with type 2 diabetes mellitus experience high rates of influenza virus infection and complications. We compared the magnitude and duration of serologic response to trivalent influenza vaccine in adults aged 50-80 with and without type 2 diabetes mellitus. Serologic response to influenza vaccination was similar in both groups: greater fold-increases in antibody titer occurred among individuals with lower pre-vaccination antibody titers. Waning of antibody titers was not influenced by diabetes status.Competing Interest StatementKKM, MPN and RZ have received research funds from Merck & Co., Inc and Pfizer, Inc. KKM and RZ have received research funds from Sanofi Pasteur, Inc. LC is currently employed by Novartis. The remaining authors report no conflicts of interest.Funding StatementThis study was supported by cooperative agreements U01 IP000471 and U01 IP000467 from the Centers for Disease Control and Prevention. The findings and conclusions in this report are those of those authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Institutional Review Boards at the University of Pittsburgh and Marshfield Clinic approved this study.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData are not publicly available at this time.

Individuals with type 2 diabetes mellitus experience high rates of influenza virus infection and complications. We compared the magnitude and duration of serologic response to trivalent influenza vaccine in adults aged 50-80 with and without type 2 diabetes mellitus. Serologic response to influenza vaccination was similar in both groups: greater fold-increases in antibody titer occurred among participants with lower pre-vaccination antibody titers. Waning of antibody titers was not influenced by diabetes status.

BACKGROUND: As the population of adults with congenital heart disease (CHD) grows, cardiologists continue to encounter patients with complex anatomies that challenge the standard treatment of care. Single ventricle Fontan palliated patients are the most complex within CHD, with a high morbidity and mortality burden. Factors driving this early demise are largely unknown. METHODS AND RESULTS: We analyzed biomarker expression in 44 stable Fontan outpatients (29.2 +/- 10.7 years, 68.2% female) seen in the outpatient Emory Adult Congenital Heart Center and compared them to 32 age, gender and race matched controls. In comparison to controls, Fontan patients had elevated levels of multiple cytokines within the inflammatory pathway including Tumor Necrosis Factor-alpha (TNF-alpha) (p < 0.001), Interleukin-6 (IL-6) (p < 0.011), Growth Derived Factor-15 (GDF-15) (p < 0.0001), beta2-macroglobulin, (p = 0.0006), stem cell mobilization: Stromal Derived Factor-1 proportional, variant (SDF-1alpha) (p = 0.006), extracellular matrix turnover: Collagen IV (p < 0.0001), neurohormonal activation: Renin (p < 0.0001), renal dysfunction: Cystatin C (p < 0.0001) and Urokinase Receptor (uPAR) (p = 0.022), cardiac injury: Troponin-I (p < 0.0004) and metabolism: Adiponectin (p = 0.0037). Within 1 year of enrollment 50% of Fontan patients had hospitalizations, arrhythmias or worsening hepatic function. GDF-15 was significantly increased in Fontan patients with clinical events (p < 0.0001). In addition, GDF-15 moderately correlated with longer duration of Fontan (r = 0.55, p = 0.01) and was elevated in atriopulmonary (AP) Fontan circulation. Finally, in a multivariate model, VEGF-D and Collagen IV levels were found to be associated with a change in MELDXI, a marker of liver dysfunction. CONCLUSION: Multiple clinical and molecular biomarkers are upregulated in Fontan patients, suggesting a state of chronic systemic dysregulation.

BACKGROUND: Invasive salmonellosis is a common community-acquired bacteremia in persons residing in sub-Saharan Africa. However, there is a paucity of data on severe typhoid fever and its associated acute and chronic host immune response and carriage. The Severe Typhoid Fever in Africa (SETA) program, a multicountry surveillance study, aimed to address these research gaps and contribute to the control and prevention of invasive salmonellosis. METHODS: A prospective healthcare facility-based surveillance with active screening of enteric fever and clinically suspected severe typhoid fever with complications was performed using a standardized protocol across the study sites in Burkina Faso, the Democratic Republic of Congo (DRC), Ethiopia, Ghana, Madagascar, and Nigeria. Defined inclusion criteria were used for screening of eligible patients for enrollment into the study. Enrolled patients with confirmed invasive salmonellosis by blood culture or patients with clinically suspected severe typhoid fever with perforation were eligible for clinical follow-up. Asymptomatic neighborhood controls and immediate household contacts of each case were enrolled as a comparison group to assess the level of Salmonella-specific antibodies and shedding patterns. Healthcare utilization surveys were performed to permit adjustment of incidence estimations. Postmortem questionnaires were conducted in medically underserved areas to assess death attributed to invasive Salmonella infections in selected sites. RESULTS: Research data generated through SETA aimed to address scientific knowledge gaps concerning the severe typhoid fever and mortality, long-term host immune responses, and bacterial shedding and carriage associated with natural infection by invasive salmonellae. CONCLUSIONS: SETA supports public health policy on typhoid immunization strategy in Africa.

BACKGROUND: Antimicrobial resistance (AMR) is a major global health concern, yet, there are noticeable gaps in AMR surveillance data in regions such as sub-Saharan Africa. We aimed to measure the prevalence of extended-spectrum beta-lactamase (ESBL) producing Gram-negative bacteria in bloodstream infections from 12 sentinel sites in sub-Saharan Africa. METHODS: Data were generated during the Typhoid Fever Surveillance in Africa Program (TSAP), in which standardized blood cultures were performed on febrile patients attending 12 health facilities in 9 sub-Saharan African countries between 2010 and 2014. Pathogenic bloodstream isolates were identified at the sites and then subsequently confirmed at a central reference laboratory. Antimicrobial susceptibility testing, detection of ESBL production, and conventional multiplex polymerase chain reaction (PCR) testing for genes encoding for beta-lactamase were performed on all pathogens. RESULTS: Five hundred and five pathogenic Gram-negative bloodstream isolates were isolated during the study period and available for further characterization. This included 423 Enterobacteriaceae. Phenotypically, 61 (12.1%) isolates exhibited ESBL activity, and genotypically, 47 (9.3%) yielded a PCR amplicon for at least one of the screened ESBL genes. Among specific Gram-negative isolates, 40 (45.5%) of 88 Klebsiella spp., 7 (5.7%) of 122 Escherichia coli, 6 (16.2%) of 37 Acinetobacter spp., and 2 (1.3%) of 159 of nontyphoidal Salmonella (NTS) showed phenotypic ESBL activity. CONCLUSIONS: Our findings confirm the presence of ESBL production among pathogens causing bloodstream infections in sub-Saharan Africa. With few alternatives for managing ESBL-producing pathogens in the African setting, measures to control the development and proliferation of AMR organisms are urgently needed.

BACKGROUND: Human immunodeficiency virus (HIV)-infected persons are at a higher risk of severe influenza. Although we have shown that a standard-dose intradermal influenza vaccine versus a standard-dose intramuscular influenza vaccine does not result in differences in hemagglutination-inhibition titers in this population, a comprehensive examination of cell-mediated immune responses remains lacking. METHODS: Serological, antigen-specific B-cell, and interleukin 2-, interferon gamma-, and tumor necrosis factor alpha-secreting T-cell responses were assessed in 79 HIV-infected men and 79 HIV-uninfected men. RESULTS: The route of vaccination did not affect the immunoglobulin A and immunoglobulin G (IgG) plasmablast or memory B-cell response, although these were severely impaired in the group with a CD4+ T-cell count of <200 cells/muL. The frequencies of IgG memory B cells measured on day 28 after vaccination were highest in the HIV-uninfected group, followed by the group with a CD4+ T-cell count of >/=200 cells/muL and the group with a CD4+ T-cell count of <200 cells/muL. The route of vaccination did not affect the CD4+ or CD8+ T-cell responses measured at various times after vaccination. CONCLUSIONS: The route of vaccination had no effect on antibody responses, antibody avidity, T-cell responses, or B-cell responses in HIV-infected or HIV-uninfected subjects. With the serological and cellular immune responses to influenza vaccination being impaired in HIV-infected individuals with a CD4+ T-cell count of <200 cells/muL, passive immunization strategies need to be explored to protect this population. CLINICAL TRIALS REGISTRATION: NCT01538940.

This study investigated the effect of cold-water hand immersion on selective attention as measured by the Stroop Color Word Test in nomorbaric normoxia and hypoxia. Ten healthy men rested for 60 min, after which they immersed their non-dominant hand into 5 degrees C water for 15 min. The interference score of the Stroop Color Word Test and thermal sensation were measured at baseline in the final 5 min of resting and in the final 5 min of cold water hand immersion. The interference score was not influenced by hypoxia but was found to be significantly improved compared to resting in both conditions during cold water hand immersion. Selective attention improved during 15 min of cold-water hand immersion, with increased thermal sensations rated as "very cool" of the immersed arm. Cold-water hand immersion may be helpful in improving cognitive function in normoxia and normobaric hypoxia.

Background: Increased facial warmth sensations could lead to thermal discomfort, and different facial regions may demonstrate concurrent temperature differences. The study aim was examining facial warmth sensitivity differences by facial region under differing environmental conditions. Methods: Twelve men had heat flux measurements of six facial regions during 30 min each of rest in thermoneutral conditions (25 degrees C, 30% relative humidity (RH)), rest in warm conditions (40 degrees C, 30% RH), and cycling at 400 W of metabolic heat production (40 degrees C, 30% RH). Results: The forehead demonstrated highest temperatures at termination of all study conditions; lowest temperatures were noted for the nose under thermoneutral conditions and chin during warmth and exercise conditions. Five of six facial regions demonstrated significant differences in warmth sensitivity, decreasing to two of six regions during warm conditions and one of six regions during exercise, with the upper lip most sensitive in all conditions. Body thermal comfort (TC) perceptions, regressed individually on mean facial temperature (Tface) vs. core temperature (Tco), indicated that Tface was significantly more related than Tco to perceived TC (p = .001). Perceived TC, regressed individually on perceived overall body thermal sensation (TS) vs. facial TS, demonstrated that Tface was significantly more related to perceived TC (p = .004). Conclusion: There were regional differences in facial warmth sensitivity together with different facial temperatures moving toward equilibration when the body is subjected to heat-producing activities. Perceptions of TC were more strongly related to Tface than to Tco or overall body TS.

This study examined whether different combinations of ambient temperature and relative humidity for the effective wet bulb globe temperature, in conjunction with two different levels of clothing adjustment factors, elicit a similar level of heat strain consistent with the current threshold limit value guidelines. Twelve healthy, physically active men performed four 15-min sessions of cycling at a fixed rate of metabolic heat production of 350 watts. Each trial was separated by a 15-min recovery period under four conditions: (1) Cotton coveralls + dry condition (WD: 45.5 degrees C dry-bulb, 15% relative humidity); (2) Cotton coveralls + humid condition (WH: 31 degrees C dry-bulb, 84% relative humidity); (3) Protective clothing + dry condition (PD: 30 degrees C dry-bulb, 15% relative humidity); and (4) Protective clothing + humid condition (PH: 20 degrees C dry-bulb, 80% relative humidity). Gloves (mining or chemical) and headgear (helmet or powered air-purifying respirator) were removed during recovery with hydration ad libitum. Rectal temperature (Tre), skin temperature (Tsk), physiological heat strain (PSI), perceptual heat strain (PeSI), and body heat content were calculated. At the end of the 2-hr trials, Tre remained below 38 degrees C and the magnitude of Tre elevation was not greater than 1 degrees C in all conditions (WD: 0.9, WH: 0.8, WH: 0.7, and PD: 0.6 degrees C). However, Tsk was significantly increased by approximately 2.1 +/- 0.8 degrees C across all conditions (all p </= 0.001). The increase in Tsk was the highest in WD followed by PD, WH, and PH conditions (all p </= 0.001). Although PSI and PeSI did not indicate severe heat strain during the 2-hr intermittent work period, PSI and PeSI were significantly increased over time (p </= 0.001). This study showed that core temperature and heat strain indices (PSI and PeSI) increased similarly across the four conditions. However, given that core temperature increased continuously during the work session, it is likely that the American Conference of Governmental Industrial Hygienist's TLV((R)) upper limit core temperature of 38.0 degrees C may be surpassed during extended work periods under all conditions.

PURPOSE: Cold-induced vasodilation (CIVD) is known to protect humans against local cold injuries and improve manual dexterity. The current study examined the effects of metabolic heat production on cold-induced vasodilation responses in normobaric hypoxia and normoxia. METHODS: Ten participants immersed their non-dominant hand into 5 degrees C water for 15 min. Minimum finger temperature (Tmin), maximum finger temperature (Tmax), onset time, amplitude, and peak time were measured before and after exercise under normoxia (21% O2) and two levels of normobaric hypoxia (17% O2 and 13% O2). RESULTS: Neither Tmin nor amplitude was affected by hypoxia. However, Tmax was significantly decreased by hypoxia while reduction in onset time and peak time trended towards significance. Tmin, Tmax, and amplitude were significantly higher during post-exercise CIVD than pre-exercise CIVD. CONCLUSION: The CIVD response may be negatively affected by the introduction of hypoxia whereas metabolic heat production via exercise may counteract adverse effects of hypoxia and improve CIVD responses.

Group A Streptococcus (GAS) infections result in a considerable under-appreciated burden of acute and chronic disease, globally. A 2018 World Health Assembly resolution calls for better control and prevention. Providing guidance on global health research needs is an important WHO activity, influencing prioritization of investments. Here, the role, status and directions in GAS vaccines research are discussed. WHO preferred product characteristics and a research and development technology roadmap, briefly presented, offer an actionable framework for vaccine development to regulatory and policy decision-making, availability and use. GAS vaccines should be considered for global prevention of the range of clinical manifestations and associated antibiotic use. Impediments related to antigen diversity, safety concerns, and the difficulty to establish vaccine efficacy against rheumatic heart disease are discussed. Demonstration of vaccine efficacy against pharyngitis and skin infections constitute key near-term strategic goals. Investments and collaborative partnerships to diversify and advance vaccine candidates are needed.

IntroductionPersonal protective equipment (PPE) recommended for use in West Africa during the Ebola outbreak increased risk for heat illness, and countermeasures addressing this issue would be valuable.Hypothesis/ProblemThe purpose of this study was to examine the physiological impact and heat perception of four different personal cooling devices (PCDs) under impermeable PPE during low-intensity exercise in a hot and humid environment using thermal manikin modeling and human testing. METHODS: Six healthy male subjects walked on a treadmill in a hot/humid environment (32 degrees C/92% relative humidity [RH]) at three metabolic equivalents (METs) for 60 minutes wearing PPE recommended for use in West Africa and one of four different personal cooling devices (PCDs; PCD1, PCD2, PCD3, and PCD4) or no PCD for control (CON). The same ensembles were tested with thermal manikin modeling software in the same conditions to compare the results. RESULTS: All PCDs seemed to reduce physiological heat stress characteristics when worn under PPE compared to CON. Both the manikin and human testing provided similar results in core temperature (Tc) and heat sensation (HS) in both magnitude and relationship. While the manikin and human data provided similar skin temperature (Tsk) characterization, Tsk estimation by the manikin seemed to be slightly over-estimated. Weight loss, as estimated by the manikin, was under-estimated compared to the human measurement. CONCLUSION: Personal cooling device use in conjunction with impermeable PPE may be advantageous in mitigating physiological and perceptual burdens of heat stress. Evaluation of PCDs worn under PPE can be done effectively via human or manikin testing; however, Tsk may be over-estimated and weight loss may be under-estimated. Thermal manikin testing of PCDs may provide fast and accurate information to persons recommending or using PCDs with PPE. QuinnT, KimJH, SeoY, CocaA. Comparison of thermal manikin modeling and human subjects' response during use of cooling devices under personal protective ensembles in the heat. Prehosp Disaster Med. 2018;33(3):279-287.

Influenza virus causes widespread, yearly epidemics by accumulating surface protein mutations to escape neutralizing antibodies established from prior exposure. In contrast to antibody epitopes, T cell mediated immunity targets influenza epitopes that are more highly conserved and have potential for cross-protection. The extent of T cell cross-reactivity between a diverse array of contemporary and historical influenza strains was investigated in ferrets challenged with 2009 pandemic H1N1 influenza or the seasonal H3N2 strain, A/Perth/16/2009. Post-challenge cell-mediated immune responses demonstrated extensive cross-reactivity with a wide variety of contemporary and historical influenza A strains as well as influenza B. Responses in peripheral blood were undetectable by 36d post-challenge, but cross-reactivity persisted in spleen. The strongest responses targeted peptides from the NP protein and demonstrated cross-reactivity in both the CD4+ and CD8+ T cell populations. Cross-reactive CD4+ T cells also targeted HA and NA epitopes, while cross-reactive CD8+ T cells targeted internal M1, NS2, and PA. T cell epitopes demonstrated extensive cross-reactivity between diverse influenza strains in outbred animals, with NP implicated as a significant antigenic target demonstrating extensive cross-reactivity for both CD4+ and CD8+ T cells.

We assessed the effect of metaboreceptor activation on whole-body evaporative heat loss (WB-EHL) in twelve men (24+/-4 years) in the early-to-late-stages of a 60-min exercise recovery in the heat. Metaboreceptor activation induced by 1-min isometric-handgrip (IHG) exercise followed by 5-min forearm ischemia to trap metabolites increased WB-EHL by 25-31% and 26-34% during the ischemic period relative to IHG-Only and Control (natural recovery only) respectively throughout recovery. We show that metaboreceptor activation enhances WB-EHL in recovery.

Machine and human subject testing of four prototype filtering facepiece respirators (FFR) and two commercial FFR was carried out utilizing recently proposed respirator test criteria that address healthcare worker-identified comfort and tolerance issues. Overall, two FFR (one prototype, one commercial model) were able to pass all eight criteria and three FFR (two prototypes, one commercial model) were able to pass seven of eight criteria. One prototype FFR was not tested against the criteria due to an inability to obtain satisfactory results on human subject quantitative respirator fit testing. Future studies, testing different models and styles of FFR against the proposed criteria, will be required to gauge the overall utility and effectiveness of the criteria in determining FFR comfort and tolerance issues that may impact user compliance and, by extension, protection.

Seo, Yongsuk, Jeremiah Vaughan, Tyler D. Quinn, Brittany Followay, Raymond Roberge, Ellen L. Glickman, and Jung-Hyun Kim. The effect of inspiratory resistance on exercise performance and perception in moderate normobaric hypoxia. High Alt Med Biol. 00:000-000, 2017. PURPOSE: Respirators are simple and efficient in protecting workers against toxic airborne substances; however, their use may limit the physical performance of workers. The purpose of this study was to determine the effect of inspiratory resistance on physical performance and breathing perception in normobaric hypoxia. METHOD: Nine healthy men wore a tight-fitting respiratory mask outfitted with one of four different inspiratory resistors (R) (0, 1.5, 4.5, 7.5 cm H2O/L/Sec) while exercising at normobaric hypoxia (17% O2) at submaximal exercise workloads of 50, 100, and 150 W on a cycle ergometer for 10 minutes each, followed by a maximal oxygen uptake (VO2max) test to exhaustion. RESULTS: Maximal power output at R7.5 was significantly lower than R0 (p = 0.016) and R1.5 (p = 0.035). Respiration rate was significantly reduced at R4.5 (p = 0.011) and R7.5 (p ≤ 0.001) compared with R0. Minute ventilation was significantly decreased in R7.5 compared with R0 (p = 0.003), R1.5 (p = 0.010), and R4.5 (p = 0.016), whereas VO2 was not significantly changed. Breathing comfort (BC) and breathing effort (BE) were significantly impaired in R7.5 (BC: p = 0.025, BE: p = 0.001) and R4.5 (BC: p = 0.007, BE: p = 0.001) compared with R0, but rating of perceived exertion (RPE) remained unchanged. CONCLUSIONS: Added inspiratory resistance limited maximal power output and increased perceptions of BC and BE in normobaric hypoxia. However, low-to-moderate inspiratory resistance did not have a deleterious effect on VO2 or RPE at submaximal or maximal exercise. Perceptual and physiological characteristics of respirators of varying inspiratory resistances should be considered by manufacturers and end users during design and respirator selection processes.

Wet bulb globe temperature (WBGT) index is used by many professionals in combination with metabolic rate and clothing adjustments to assess whether a heat stress exposure is sustainable. The progressive heat stress protocol is a systematic method to prescribe a clothing adjustment value (CAV) from human wear trials, and it also provides an estimate of apparent total evaporative resistance (Re,T,a). It is clear that there is a direct relationship between the two descriptors of clothing thermal effects with diminishing increases in CAV at high Re,T,a. There were data to suggest an interaction of CAV and Re,T,a with relative humidity at high evaporative resistance. Because human trials are expensive, manikin data can reduce the cost by considering the static total evaporative resistance (Re,T,s). In fact, as the static evaporative resistance increases, the CAV increases in a similar fashion as Re,T,a. While the results look promising that Re,T,s can predict CAV, some validation remains, especially for high evaporative resistance. The data only supports air velocities near 0.5 m/s.

BACKGROUND: Hypoxia and exercise each exhibit opposing effects on executive function, and the mechanisms for this are not entirely clear. This study examined the influence of cerebral oxygenation and perfusion on executive function during exercise and recovery in normobaric hypoxia (NH) and normoxia (N). METHODS: There were 18 subjects who completed cycling trials in NH (12.5% FIo2) and N (20.93% FIo2). Right prefrontal cortex (PFC) oxyhemoglobin (O2Hb) and middle cerebral artery blood velocity (MCAbv) were collected during executive function challenges [mathematical processing and running memory continuous performance task (RMCPT)] at baseline, following 30 min of acclimation, during 20 min of cycling (60% Vo2max), and at 1, 15, 30, and 45 min following exercise. RESULTS: Results indicated effects of time for Math, RMCPT, and O2Hb; but not for MCAbv. Results also indicated effects of condition for O2Hb. Math scores were improved by 8.0% during exercise and remained elevated at 30 min of recovery (12.5%), RMCPT scores significantly improved at all time points (7.5-11.9%), and O2Hb increased by 662.2% and 440.9% during exercise in N and NH, respectively, and remained elevated through 15 min of recovery in both conditions. DISCUSSION: These results support the influence of PFC oxygenation and perfusion on executive function during exercise and recovery in N and NH.Stavres J, Gerhart HD, Kim J-H, Glickman EL, Seo Y. Cerebral hemodynamics and executive function during exercise and recovery in normobaric hypoxia. Aerosp Med Hum Perform 2017; 88(10):911-917.

Twelve subjects wore an N95 filtering facepiece respirator (N95 FFR), one tight-fitting full facepiece powered air-purifying respirator (PAPR), two loose-fitting PAPRs, and one elastomeric/PAPR hybrid for 1 hr each during treadmill walking at 5.6 km/hr while undergoing physiological and subjective response monitoring. No significant interaction (p ≥ .05) was noted between the five respirators in heart rate, respiratory rate, oxygen saturation, transcutaneous carbon dioxide, and perceptions of breathing effort or discomfort, exertion, facial heat, and overall body heat. Respirator deadspace heat/humidity were significantly greater for the N95 FFR, whereas tympanic forehead skin temperatures were significantly greater for the hybrid PAPR. Temperature of the facial skin covered by the respirator was equivalent for the N95 FFR and hybrid PAPR, and both were significantly higher than for the other three PAPRs. Perception of eye dryness was significantly greater for a tight-fitting full facepiece PAPR than the N95 FFR and hybrid PAPR. At a low-moderate work rate over 1 hr, effects on cardiopulmonary variables, breathing perceptions, and facial and overall body heat perceptions did not differ significantly between the four PAPRs and a N95 FFR, but the tight-fitting, full facepiece PAPR increased perceptions of eye dryness. The two loose-fitting PAPRs and the full facepiece tight-fitting PAPR ameliorated exercise-induced increases in facial temperature, but this did not translate to improved perception of facial heat and overall body heat.

Sporadic, yet frequent human infections with avian H5N1 influenza A viruses continue to pose a potential pandemic threat. Poor immunogenicity of unadjuvanted H5N1 vaccines warrants developing novel adjuvants and formulations as well as alternate delivery systems to improve their immunogenicity and efficacy. Here, we show that Protollin, a nasal adjuvant composed of Neisseria meningitides outer membrane proteins non-covalently linked to Shigella flexneri 2a lipopolysaccharide, is a potent nasal adjuvant for an inactivated split virion H5N1 clade 1 A/Viet Nam1203/2004 (A/VN/1203/04) vaccine in a mouse model. Protollin-adjuvanted vaccines elicited enhanced serum protective hemagglutination inhibition titers, mucosal IgA responses, and H5N1-specific cell-mediated immunity that resulted in complete protection against a lethal challenge with a homologous virus as well as a heterologous clade 2 virus A/Indonesia/05/2005 (A/IN/05/05). Detailed analysis of adaptive immunity revealed that Protollin increased the frequency of lymphoid- as well as local tissue-resident antibody-secreting cells, local germinal center reaction of B cells, broad-spectrum of CD4 T cell response. Our findings suggest that nasal delivery of H5N1 vaccine with Protollin adjuvant can overcome the poor immunogenicity of H5N1 vaccines, induce both cellular and humoral immune responses, enhance protection against challenge with clade 1 and clade 2 H5N1 viruses and achieve significant antigen dose-sparing.

Purpose: to determine the correlation of umbilical temperatures (Tumb) with simultaneously recorded chest wall temperature (Tchest) and rectal temperature (Trectal) in adults during rest, heat exposure and exercise. Methods: A total of 28 healthy men, wearing different types of clothing (athletic garb, a spandex full body heating garment, firefighter bunker gear) had average and peak umbilical, chest wall and rectal temperature measurements taken during sedentary temperature stabilisation stages, heat exposure periods and active exercise phases. Results: Curvilinear relationships were noted between Tchest and Tumb compared with Trectal and their association became noticeably positive and linear at approximately 35.5degreeC. Polynomial regression analysis of Trectal with linear and quadratic forms of Tchest and Tumb indicated an overall R2 of 0.657 and 0.767, respectively. Bivariate analysis of a restricted data set (where Tchest and Tumb>35.5degree), indicated that Tumb was significantly associated with Trectal (raverage=0.710, p<0.001; rpeak=0.841, p<0.001) and Tchest was also significantly associated with Trectal, but less so (raverage=0.570, p<0.001; rpeak=0.699, p<0.001). Conclusions: the umbilicus offers a non-invasive, peripheral site for measurement of temperature that more closely correlated with body core temperature than Tchest when core temperature was >35.5degreeC.

Seo, Yongsuk, Hayden D. Gerhart, Jeremiah Vaughan, Jung-Hyun Kim, and Ellen L. Glickman. Does acute normobaric hypoxia induce anapyrexia in adult humans? High Alt Med Biol 00:000-000, 2017.-Exposure to hypoxia is known to induce a reduction in core body temperature as a protective mechanism, which has been shown in both animals and humans. The purpose of this study was to test if acute exposure to normobaric hypoxia (NH) induces anapyrexia in adult humans in association with decreased peripheral oxygen saturation (SpO2). Ten healthy male subjects were seated in atmospheres of normobaric normoxia 21% (NN21), NH 17% (NH17), and 13% (NH13) O2 for 60 minutes in a counterbalanced manner. Rectal temperature (Tre) was continuously monitored together with the quantification of metabolic heat production (MHP) and body heat storage (S). Baseline physiological measurements showed no differences between the three conditions. SpO2 was significantly decreased in NH17 and NH13 compared with NN21 (p ≤ 0.001). Tre decreased following 60 minutes of resting in all conditions, but, independent of the conditions, showed no association between Tre and levels of hypoxic SpO2. There was also no significant difference in either MHP or S between conditions. The present results showed no evidence of hypoxia-induced anapyrexia in adult humans during 1 hour of resting after exposure to NH either at 13% or 17% O2.

OBJECTIVE: Cooling devices (CDs) worn under personal protective equipment (PPE) can alleviate some of the heat stress faced by health care workers responding to the Ebola outbreak in West Africa. METHODS: Six healthy, young individuals were tested while wearing 4 different CDs or no cooling (control) under PPE in an environmental chamber (32 degrees C/92% relative humidity) while walking (3 METs, 2.5 mph, 0% grade) on a treadmill for 60 minutes. Exercise was preceded by a 15-minute stabilization period and a 15-minute donning period. RESULTS: The control condition resulted in a significantly higher rectal temperature (Tre) at the end of the exercise than did all CD conditions (CD1, P=0.004; CD2, P=0.01; CD3, P=0.000; CD4, P=0.000) with CD1 and CD2 resulting in a higher Tre than CD3 and CD4 (P<0.05). The control condition resulted in a higher heart rate (HR) at the end of exercise than did the CD3 (P=0.01) and CD4 (P=0.009) conditions, whereas the HR of the CD1 and CD2 conditions was higher than that of the CD3 and CD4 conditions (P<0.05). Weight loss in the control condition was higher than in the CD3 (P=0.003) and CD4 (P=0.01) conditions. Significant differences in subjective measurements of thermal stress were found across conditions and time. CONCLUSIONS: Use of CDs can be advantageous in decreasing the negative physiological and subjective responses to the heat stress encountered by health care workers wearing PPE in hot and humid environments. (Disaster Med Public Health Preparedness. 2017;page 1 of 7).

OBJECTIVE: Personal protective equipment (PPE) provides health care workers with a barrier to prevent human contact with viruses like Ebola and potential transmission of the disease. However, PPE can also introduce an additional physiological burden from potentially increased heat stress. This study evaluated the human physiological and subjective responses to continuous light exercise within environmental conditions similar to those in West Africa while wearing 3 different, commonly used PPE ensembles (E1, E2, and E3). METHODS: Six healthy individuals were tested in an environmental chamber (32 degrees C, 92% relative humidity) while walking (3 METs, 2.5 mph, 0% incline) on a treadmill for 60 minutes. All subjects wore medical scrubs and PPE items. E1 also had a face shield and fluid-resistant surgical gown; E2 additionally included goggles, coverall, and separate hood; and E3 also contained a highly impermeable coverall, separate hood, and surgical mask cover over the N95 respirator. RESULTS: Heart rate and core temperature at the end of the exercise were significantly higher for E2 and E3 than for E1. Subjective perceptions of heat and exertion were significantly higher for E2 and E3 than for E1. CONCLUSIONS: Heat stress and PPE training, as well as the implementation of a work-to-rest ratio that avoids dehydration and possible heat stress issues, are recommended. (Disaster Med Public Health Preparedness. 2017;page 1 of 7).

Tunneling nanotubes (TNTs) represent a novel route of intercellular communication. While previous work has shown that TNTs facilitate the exchange of viral or prion proteins from infected to naive cells, it is not clear whether the viral genome is also transferred via this mechanism and further, whether transfer via this route can result in productive replication of the infectious agents in the recipient cell. Here we present evidence that lung epithelial cells are connected by TNTs, and in spite of the presence of neutralizing antibodies and an antiviral agent, Oseltamivir, influenza virus can exploit these networks to transfer viral proteins and genome from the infected to naive cell, resulting in productive viral replication in the naive cells. These observations indicate that influenza viruses can spread using these intercellular networks that connect epithelial cells, evading immune and antiviral defenses and provide an explanation for the incidence of influenza infections even in influenza-immune individuals and vaccine failures.

The association of seasonal trivalent influenza vaccine (TIV) with increased infection by 2009 pandemic H1N1 (A(H1N1)pdm09) virus, initially observed in Canada, has elicited numerous investigations on the possibility of vaccine-associated enhanced disease, but the potential mechanisms remain largely unresolved. Here, we investigated if prior immunization with TIV enhanced disease upon A(H1N1)pdm09 infection in mice. We found that A(H1N1)pdm09 infection in TIV-immunized mice did not enhance the disease, as measured by morbidity and mortality. Instead, TIV-immunized mice cleared A(H1N1)pdm09 virus and recovered at an accelerated rate compared to control mice. Prior TIV immunization was associated with potent inflammatory mediators and virus-specific CD8 T cell activation, but efficient immune regulation, partially mediated by IL-10R-signaling, prevented enhanced disease. Furthermore, in contrast to suggested pathological roles, pre-existing non-neutralizing antibodies (NNAbs) were not associated with enhanced virus replication, but rather with promoted antigen presentation through FcR-bearing cells that led to potent activation of virus-specific CD8 T cells. These findings provide new insights into interactions between pre-existing immunity and pandemic viruses.

BACKGROUND: Influenza viruses gradually accumulate point mutations, reducing effectiveness of prior immune protection. METHODS: Children ages 9-14 received 2010-2011 trivalent inactivated influenza vaccine (TIV). Vaccination history, hemagglutination-inhibition (HI) titers, and cell-mediated immune responses were assessed, investigatng cross-reactivity with past and future strains. RESULTS: 2010-2011 TIV induced significant T cell responses and HI titers ≥160 with fold-rise ≥4 in the majority of children, maintaining titers ≥100 over 7 months. Pre-existing memory B cells in these children differentiated quickly to antibody secreting cells to the new vaccine antigens. Children vaccinated the previous year maintained high HI titers well into 2010, demonstrating elevated A/Perth/16/2009 (A/Perth/16) HI titers, the future H3N2 (2010-2011) component. Prior vaccination enhanced CD8+ responses to A/Perth/16. Children vaccinated with the prior 2009-2010 seasonal vaccine also demonstrated higher pre-existing CD4+CD69+IFN-gamma+ T cells to 2009 pandemic H1N1. Children previously vaccinated with 2009-2010 seasonal influenza vaccine also showed greater expansion of CD8+CD69+TNF-alpha+ T cells to pandemic H1N1 upon vaccination in the 2010-2011 season than those who were not previously vaccinated. CONCLUSIONS: Seasonal influenza viruses continuously drift to circumvent protective immunity, however, conserved epitopes provide immunological cross-reactivity in children through either vaccination directly or through prime/boost in the prior influenza season.

BACKGROUND: Emergence of drifted influenza A(H3N2) viruses resulted in reduced vaccine effectiveness in all age groups during the 2014-15 influenza season. In children, inactivated influenza vaccine (IIV) elicited neutralizing antibodies (Abs) against drifted strains at significantly lower levels than against vaccine strain. Little is known about cross-reactivity of cell-mediated immunity (CMI) against drifted strains in children. METHODS: Children aged 3-17 years (N=48) received IIV during the 2014-15 influenza season. Peripheral blood mononuclear cells, collected at pre-and post-vaccination (d0, d7, d21) were evaluated for induction of cross-reactive plasmablasts, memory B cells, and cytokine-secreting CD4 and CD8 T cells against the vaccine and drifted A(H3N2) viruses by ELISPOT assay and flow cytometry. RESULTS: IIV increased frequencies of plasmablasts and memory B cells. The overall induction of the T cell response was not significant. Both B cell and T cell responses showed significant cross-reactivity against A(H3N2) viruses. Age and pre-existing immunity affected virus-specific plasmablast responses and fold-rise of T cell responses, respectively. Proportion of TH1-prone (IFNgamma or TNFalpha-secreting) CD4 T cell responses also increased with age. CONCLUSIONS: In children aged 3-17 years, B and T cell responses following IIV receipt showed significant cross-reactivity against A(H3N2) viruses during a vaccine mismatch season.

High-dose (HD) influenza vaccine shows improved relative efficacy against influenza disease compared to standard-dose (SD) vaccine in individuals 65years. This has been partially credited to superior serological responses, but a comprehensive understanding of cell-mediated immunity (CMI) of HD vaccine remains lacking. In the current study, a total of 105 participants were randomly administered HD or SD vaccine and were evaluated for serological responses. Subsets of the group (n=12-26 per group) were evaluated for B and T cell responses at days 0, 7, 14 and 28 post-vaccination by flow cytometry or ELISPOT assay. HD vaccine elicited significantly higher hemagglutination inhibition (HI) titers than SD vaccine at d28, but comparable titers at d365 post-vaccination. HD vaccine also elicited higher vaccine-specific plasmablast responses at d7 post-vaccination than SD vaccine. However, long-lived memory B cell induction, cytokine-secreting T cell responses and persistence of serological memory were comparable regardless of vaccine dose. More strategies other than increased Ag amount may be needed to improve CMI in older adults. TRIAL REGISTRATION: ClinicalTrials.gov NCT 01189123.

In order to better understand inflammation associated with influenza virus infection, we measured cell trafficking, via flow cytometry, to various tissues in the ferret model following infection with an A(H3N2) human seasonal influenza virus (A/Perth/16/2009). Changes in immune cells were observed in the blood, bronchoalveolar lavage fluid, and spleen, as well as lymph nodes associated with the site of infection or distant from the respiratory system. Nevertheless clinical symptoms were mild, with circulating leukocytes exhibiting rapid, dynamic, and profound changes in response to infection. Each of the biological compartments examined responded differently to influenza infection. Two days after infection, when infected ferrets showed peak fever, a marked, transient lymphopenia and granulocytosis were apparent in all infected animals. Both draining and distal lymph nodes demonstrated significant accumulation of T cells, B cells, and granulocytes at days 2 and 5 post-infection. CD8+ T cells significantly increased in spleen at days 2 and 5 post-infection; CD4+ T cells, B cells and granulocytes significantly increased at day 5. We interpret our findings as showing that lymphocytes exit the peripheral blood and differentially home to lymph nodes and tissues based on cell type and proximity to the site of infection. Monitoring leukocyte homing and trafficking will aid in providing a more detailed view of the inflammatory impact of influenza virus infection.