A broadly neutralizing human monoclonal antibody generated from transgenic mice immunized with HCMV particles limits virus infection and proliferation.

Human cytomegalovirus (HCMV) is a ß-herpesvirus that poses severe disease risk for immunocompromised patients who experience primary infection or reactivation. Development and optimization of safe and effective anti-HCMV therapeutics is of urgent necessity for the prevention and treatment of HCMV-associated diseases in diverse populations. The use of neutralizing monoclonal antibodies (mAbs) to limit HCMV infection poses a promising therapeutic strategy, as anti-HCMV mAbs largely inhibit infection by targeting virion glycoprotein complexes. In contrast, the small-molecule compounds currently approved for patients (e.g., ganciclovir, letermovir, and maribavir) target later stages of the HCMV life cycle. Here, we present a broadly neutralizing human mAb, designated 1C10, elicited from a VelocImmune mouse immunized with infectious HCMV particles. Clone 1C10 neutralizes infection after virion binding to cells by targeting gH/gL envelope complexes and potently reduces infection of diverse HCMV strains in fibroblast, trophoblast, and epithelial cells. Antibody competition assays found that 1C10 recognizes a region of gH associated with broad neutralization and binds to soluble pentamer in the low nanomolar range. Importantly, 1C10 treatment significantly reduced virus proliferation in both fibroblast and epithelial cells. Further, the combination treatment of mAb 1C10 with ganciclovir reduced HCMV infection and proliferation in a synergistic manner. This work characterizes a neutralizing human mAb for potential use as a HCMV treatment, as well as a possible therapeutic strategy utilizing combination-based treatments targeting disparate steps of the viral life cycle. Collectively, the findings support an antibody-based therapy to effectively treat patients at risk for HCMV-associated diseases. IMPORTANCE: Human cytomegalovirus is a herpesvirus that infects a large proportion of the population and can cause significant disease in diverse patient populations whose immune systems are suppressed or compromised. The development and optimization of safe anti-HCMV therapeutics, especially those that have viral targets and inhibition mechanisms different from current HCMV treatments, are of urgent necessity to better public health. Human monoclonal antibodies (mAbs) that prevent HCMV entry of cells were identified by immunizing transgenic mice and screened for broad and effective neutralization capability. Here, we describe one such mAb, which was found to target gH/gL envelope complexes and effectively limit HCMV infection and dissemination. Further, administration of the antibody in combination with the antiviral drug ganciclovir inhibited HCMV in a synergistic manner, highlighting this approach and the use of anti-HCMV mAbs more broadly, as a potential therapeutic strategy for the treatment of diverse patient populations.

Defeating depolarizing fields with artificial flux closure in ultrathin ferroelectrics.

Material surfaces encompass structural and chemical discontinuities that often lead to the loss of the property of interest in so-called dead layers. It is particularly problematic in nanoscale oxide electronics, where the integration of strongly correlated materials into devices is obstructed by the thickness threshold required for the emergence of their functionality. Here we report the stabilization of ultrathin out-of-plane ferroelectricity in oxide heterostructures through the design of an artificial flux-closure architecture. Inserting an in-plane-polarized ferroelectric epitaxial buffer provides the continuity of polarization at the interface; despite its insulating nature, we observe the emergence of polarization in our out-of-plane-polarized model of ferroelectric BaTiO3 from the very first unit cell. In BiFeO3, the flux-closure approach stabilizes a 251° domain wall. Its unusual chirality is probably associated with the ferroelectric analogue to the Dzyaloshinskii-Moriya interaction. We, thus, see that in an adaptively engineered geometry, the depolarizing-field-screening properties of an insulator can even surpass those of a metal and be a source of functionality. This could be a useful insight on the road towards the next generation of oxide electronics.

Arterial blood gas analysis or venous blood gas analysis for adult hospitalised patients with respiratory presentations: a systematic review.

BACKGROUND: Identification of hypoxaemia and hypercapnia is essential for the diagnosis and treatment of acute respiratory failure. While arterial blood gas (ABG) analysis is standard for PO2 and PCO2 measurement, venous blood gas (VBG) analysis is increasingly used as an alternative. Previous systematic reviews established that VBG reporting of PO2 and PCO2 is less accurate, but the impacts on clinical management and patient outcomes are unknown. AIMS: This study aimed to systematically review available evidence of the clinical impacts of using ABGs or VBGs and examine the arteriovenous difference in blood gas parameters. METHODS: A comprehensive search of the MEDLINE, Embase and Cochrane Library databases since inception was conducted. Included studies were prospective or cross-sectional studies comparing peripheral ABG to peripheral VBG in adult non-critical care inpatients presenting with respiratory symptoms. RESULTS: Of 15 119 articles screened, 15 were included. No studies were found that examined clinical impacts resulting from using VBG compared to ABG. Included studies focused on the agreement between ABG and VBG measurements of pH, PO2, PCO2 and HCO3 -. Due to the heterogeneity of the included studies, qualitative evidence synthesis was performed. While the arteriovenous difference in pH and HCO3 - was generally predictable, the difference in PO2 and PCO2 was more significant and less predictable. CONCLUSIONS: Our study reinforces the notion that VBG is not comparable to ABG for physiological measurements. However, a key revelation from our research is the significant lack of data regarding the clinical implications of using VBG instead of ABG, a common scenario in clinical practice. This highlights a critical knowledge gap.

Trends in Physician Payments for Hand Surgery Consultations and Clinic Visits.

PURPOSE: The primary objective of this study was to identify the trends in reimbursement for hand surgeons for new patient visits, outpatient consultations, and inpatient consultations from the years 2010-2018. In addition, we sought to investigate the influence of payer mix and coding level of service on physician reimbursement in these settings. METHODS: The PearlDiver Patients Records Database was used to identify clinical encounters and their respective physician reimbursements for analysis within this study. This database was queried using Current Procedural Terminology codes to identify relevant clinical encounters for inclusion, filtered for the presence of valid demographic information and by physician specialty for the presence of a hand surgeon, and tracked by primary diagnoses. Cost data were then calculated and analyzed regarding the payer type and level of care. RESULTS: In total, 156,863 patients were included in this study. The mean reimbursement for inpatient consultations, outpatient consultations, and new patient encounters increased by 92.75% ($134.85 to $259.93), 17.80% ($161.33 to $190.04), and 26.78% ($102.58 to $130.05), respectively. When normalized to 2018 dollars to adjust for inflation, the percent increases were 67.38%, 2.24%, and 10.09%, respectively. Commercial insurance reimbursed hand surgeons to a greater degree than any other payer type. Mean physician reimbursement differed depending on the level of service billed, with the level of service V reimbursing 4.41 times more than the level of service I visits for new outpatient visits, 3.66 times more for new outpatient consultations, and 3.04 times more for new inpatient consultations. CONCLUSIONS: This study helps to provide physicians, hospitals, and policymakers with objective information regarding the trends in reimbursement to hand surgeons. Although this study indicates increasing reimbursements for consultations and new patient visits to hand surgeons, the margins shrink when adjusted for inflation. LEVEL OF EVIDENCE: Economic Analysis IV.

Real-world opioid prescription to patients with serious, non-malignant, respiratory illnesses and chronic breathlessness.

BACKGROUND: Chronic breathlessness is a disabling symptom that is often under-recognised and challenging to treat despite optimal disease-directed therapy. Low-dose, oral opioids are recommended to relieve breathlessness, but little is known regarding long-term opioid prescription in this setting. AIM: To investigate the long-term efficacy of, and side-effects from, opioids prescribed for chronic breathlessness to patients with advanced, non-malignant, respiratory diseases. METHODS: A prospective cohort study of all patients managed by the advanced lung disease service, an integrated respiratory and palliative care service, at the Royal Melbourne Hospital from 1 April 2013 to 3 March 2020. RESULTS: One hundred and nine patients were prescribed opioids for chronic breathlessness. The median length of opioid use was 9.8 (interquartile range (IQR) = 2.8-19.8) months. The most commonly prescribed initial regimen was an immediate-release preparation (i.e. Ordine) used as required (37; 33.9%). For long-term treatment, the most frequently prescribed regimen included an extended-release preparation with an as needed immediate-release (37; 33.9%). The median dose prescribed was 12 (IQR = 8-28) mg oral morphine equivalents/day. Seventy-one (65.1%) patients reported a subjective improvement in breathlessness. There was no significant change in the mean modified Medical Research Council dyspnoea score (P = 0.807) or lung function measurements (P = 0.086-0.727). There was no association between mortality and the median duration of opioid use (P = 0.201) or dose consumed (P = 0.130). No major adverse events were reported. CONCLUSION: Within this integrated respiratory and palliative care service, patients with severe, non-malignant respiratory diseases safely used long-term, low-dose opioids for breathlessness with subjective benefits reported and no serious adverse events.

Perioperative Opioid Analgesics and Hallux Valgus Correction Surgery: Trends, Risk Factors for Prolonged Use and Complications.

In the setting of an opioid epidemic, this study aims to provide evidence on opioid use trends, risk factors for prolonged use, and complications from perioperative opioid consumption in hallux valgus surgery. A national database was queried for patients who underwent hallux valgus correction. Regression analysis identified: (1) risk factors for prolonged postoperative narcotic use; and (2) association between preoperative/prolonged postoperative narcotic use and postoperative complications. A linear regression analysis was used to determine trends. About 20,749 patients were included, of which 3464 patients were prescribed narcotics preoperatively and 4339 were identified as prolonged postoperative narcotic prescription users. Preoperative prescriptions were identified as risk factors for prolonged use. Perioperative narcotic use was observed to be a risk factor for poor outcomes. About 21% of patients were identified as prolonged postoperative narcotic prescription users. Patients undergoing hallux valgus corrective surgery should be counseled regarding their increased risk of complications when using narcotics.

Association between the use of balanced fluids and outcomes in critically ill children: a before and after study.

BACKGROUND: Hyperchloremia and chloride load have been associated with worse clinical outcomes in critically ill patients. We sought to evaluate the electrolyte profile and clinical outcomes associated with a unit-wide transition from saline to balanced fluids for resuscitation and maintenance fluids in a pediatric intensive care unit (PICU). METHODS: A before and after analysis of all patients admitted to the PICU in a large, urban, academic hospital between August 2018 and March 2020. The transition from the use of saline to the use of balanced fluids for both resuscitation and maintenance fluid as standard care occurred in June 2019. The primary outcome was day 3 acute kidney injury (AKI). The secondary outcomes included mortality, ventilator-free days (VFDs), need for renal replacement therapy (RRT), hospital length of stay (LOS), and electrolyte abnormalities. RESULTS: Overall, 2863 patients (47% female) with a day 3 AKI rate of 12.9% (n = 130) and a mortality rate of 2.8% (n = 79) were included. After adjusting for confounders (age, PRISM III, mechanical ventilation, and immunocompromised state, septic shock), there were no significant differences in the odds of day 3 AKI (pre 13%, post 12.5%; adjusted odds ratio [aOR] 0.96, 95%CI 0.65-1.42). There were no differences in the secondary outcomes. The post-intervention period had fewer patients with hyperchloremia (pre 15.5% vs. post 10.4%, p = < 0.0001) and hyperkalemia (pre 3.2% vs. post 1.4%, p = 0.02) and more patients with hypochloremia (pre 9.5% vs. post 14.4%, p = < 0.0001) and hypokalemia (pre 38.2% vs. post 47.2%, p = < 0.0001). In reference to the normochloremic cohort, the hypochloremic cohort had an increase in day 3 AKI, need for RRT, hyperchloremia, and hyperkalemia, and a decrease in hypokalemia; and the hyperchloremic cohort had an increase in VFD and a decrease in hospital LOS. CONCLUSIONS: Following a unit-wide implementation of balanced fluids as standard care, there were no differences in rates of day 3 AKI or other clinical outcomes. However, there were lower rates of hyperkalemia and hyperchloremia and higher rates of hypokalemia and hypochloremia. Further evaluation of the effect of balanced fluids and the clinical significance of electrolyte abnormalities in critically ill children is needed.

Predicting Treatment Success with Facet Syndrome: An Algorithm to Predict Lumbar Radiofrequency Ablation Responders in a Military Population.

OBJECTIVE: Radiofrequency ablation (RFA) of the medial branch nerve is a commonly performed procedure for patients with facet syndrome. RFA has previously been demonstrated to provide long-term functional improvement in approximately 50% of patients, including those who had significant pain relief after diagnostic medial branch block. We sought to identify factors associated with success of RFA for facet pain. DESIGN: Active-duty military patients who underwent lumbar RFA (L3, L4, and L5 levels) over a 3-year period were analyzed. Defense and Veterans Pain Rating Scale (DVPRS) and Oswestry Disability Index (ODI) scores were assessed the day of procedure and at the 2-month and 6-month follow-up. These data were analyzed to identify associations between patient demographics, pain, and functional status and patients' improvement after RFA, with a primary outcome of ODI improvement and a secondary outcome of pain reduction. RESULTS: Higher levels of starting functional impairment (starting ODI scores of 42.9 vs. 37.5; P = 0.0304) were associated with a greater likelihood of improvement in functional status 6 months after RFA, and higher starting pain scores (DVPRS pain scores of 6.1 vs. 5.1; P < 0.0001) were associated with a higher likelihood that pain scores would improve 6 months after RFA. A multivariate logistic regression was then used to develop a scoring system to predict improvement after RFA. The scoring system generated a C-statistic of 0.764, with starting ODI, pain scores, and both gender and smoking history as independent variables. CONCLUSIONS: This algorithm compares favorably to that of diagnostic medial branch block in terms of prediction accuracy (C-statistic of 0.764 vs. 0.57), suggesting that its use may improve patient selection in patients who undergo RFA for facet syndrome.

Measurement of bioactive osteocalcin in humans using a novel immunoassay reveals association with glucose metabolism and ß-cell function.

Osteocalcin (OCN) is a bone-derived hormone involved in the regulation of glucose metabolism. In serum, OCN exists in carboxylated and uncarboxylated forms (ucOCN), and studies in rodents suggest that ucOCN is the bioactive form of this hormone. Whether this is also the case in humans is unclear, because a reliable assay to measure ucOCN is not available. Here, we established and validated a new immunoassay (ELISA) measuring human ucOCN and used it to determine the level of bioactive OCN in two cohorts of overweight or obese subjects, with or without type 2 diabetes (T2D). The ELISA could specifically detect ucOCN concentrations ranging from 0.037 to 1.8 ng/mL. In a first cohort of overweight or obese postmenopausal women without diabetes (n = 132), ucOCN correlated negatively with fasting glucose (r = -0.18, P = 0.042) and insulin resistance assessed by the homeostatic model assessment of insulin resistance (r = -0.18, P = 0.038) and positively with insulin sensitivity assessed by a hyperinsulinemic-euglycemic clamp (r = 0.18, P = 0.043) or insulin sensitivity index derived from an oral glucose tolerance test (r = 0.26, P = 0.003). In a second cohort of subjects with severe obesity (n = 16), ucOCN was found to be lower in subjects with T2D compared with those without T2D (2.76 ± 0.38 versus 4.52 ± 0.06 ng/mL, P = 0.009) and to negatively correlate with fasting glucose (r = -0.50, P = 0.046) and glycated hemoglobin (r = -0.57, P = 0.021). Moreover, the subjects with ucOCN levels below 3 ng/mL had a reduced insulin secretion rate during a hyperglycemic clamp (P = 0.03). In conclusion, ucOCN measured with this novel and specific assay is inversely associated with insulin resistance and ß-cell dysfunction in humans.

Associated Morbidity After the Percutaneous Release of the Medial Collateral Ligament for Knee Arthroscopy.

PURPOSE: To summarize available data on the morbidity associated with percutaneous release of the medial collateral ligament (MCL) of the knee during arthroscopy via a "pie-crusting" technique. METHODS: A search of the literature was performed using the MEDLINE and Web of Science databases to identify studies examining the morbidity of percutaneous MCL release during arthroscopy. Only English-language articles were included; technical articles and studies not focused on the use of this technique were omitted. Two independent reviewers performed the literature search, data extraction, and quality assessment. The outcomes analyzed included resultant knee instability, functional outcome scores, visual analog scale pain scores, and saphenous nerve or greater saphenous vein injury. RESULTS: Six studies met the eligibility criteria. The studies included a total of 234 knees undergoing MCL release, with a mean patient age of 41.1 years. This MCL release typically generated grade I MCL laxity, which usually diminished or resolved over time and did not require brace application. The functional outcome scores of patients undergoing MCL release did not differ from those of patients undergoing the same procedure without MCL release. Postoperative pain was not significantly different between patients who underwent MCL release and those who did not. There was a 0% incidence of injury to the saphenous nerve or greater saphenous vein with MCL release in the included studies. CONCLUSIONS: Percutaneous MCL release during knee arthroscopy is a method of increasing the medial tibiofemoral joint space without causing any significant short- or long-term complications including residual valgus instability, pain, loss of function, or damage to surrounding structures. LEVEL OF EVIDENCE: Level IV, systematic review of Level IV studies.

Granulocytic Sarcoma: A Rare Cause of Wrist Pain.

Septic, inflammatory, or crystal-induced arthritis are common etiologies of wrist pain without antecedent trauma associated with pain, loss of motion, swelling, redness, and warmth. In this report, we detail the case of granulocytic sarcoma of the wrist that presented as acute wrist pain, swelling, and limitation in motion. Granulocytic sarcoma is an exceedingly rare extramedullary tumor associated with acute myeloblastic leukemia. It may be found in any part of the body; however, upper extremity involvement is uncommon. To our knowledge, this is the first description of granulocytic sarcoma occurring in the wrist joint.

Integrated respiratory and palliative care leads to high levels of satisfaction: a survey of patients and carers.

BACKGROUND: The Advanced Lung Disease Service is a unique, new model of integrated respiratory and palliative care, which aims to address the unmet needs of patients with advanced, non-malignant, respiratory diseases. This study aimed to explore patients' and carers' experiences of integrated palliative care and identify valued aspects of care. METHODS: All current patients of the integrated service and their carers were invited to complete a confidential questionnaire by post or with an independent researcher. RESULTS: Eighty-eight responses were received from 64 (80.0%) eligible patients and from 24 (60%) eligible carers. Most participants (84, 95.5%) believed the integrated service helped them to manage breathlessness and nearly all participants (87, 98.9%) reported increased confidence managing symptoms. One third of patients (34.4%) had received a nurse-led domiciliary visit, with nearly all regarding this as helpful. Most participants believed the integrated respiratory and palliative care team listened to them carefully (87, 98.9%) with opportunities to express their views (88, 100%). Highly valued aspects of the service were continuity of care (82, 93.2%) and long-term care (77, 87.5%). Three quarters of participants (66, 75.0%) rated their care as excellent, with 20.5% rating it as very good. Nearly all (87, 98.9%) participants reported that they would recommend the service to others. CONCLUSIONS: Patients and carers expressed high levels of satisfaction with this model of integrated respiratory and palliative care. Continuity of care, high quality communication and feeling cared for were greatly valued and highlight simple but important aspects of care for all patients.

Strategic Response to an Outbreak of Circulating Vaccine-Derived Poliovirus Type 2 - Syria, 2017-2018.

Since the 1988 inception of the Global Polio Eradication Initiative (GPEI), progress toward interruption of wild poliovirus (WPV) transmission has occurred mostly through extensive use of oral poliovirus vaccine (OPV) in mass vaccination campaigns and through routine immunization services (1,2). However, because OPV contains live, attenuated virus, it carries the rare risk for reversion to neurovirulence. In areas with very low OPV coverage, prolonged transmission of vaccine-associated viruses can lead to the emergence of vaccine-derived polioviruses (VDPVs), which can cause outbreaks of paralytic poliomyelitis. Although WPV type 2 has not been detected since 1999, and was declared eradicated in 2015,* most VDPV outbreaks have been attributable to VDPV serotype 2 (VDPV2) (3,4). After the synchronized global switch from trivalent OPV (tOPV) (containing vaccine virus types 1, 2, and 3) to bivalent OPV (bOPV) (types 1 and 3) in April 2016 (5), GPEI regards any VDPV2 emergence as a public health emergency (6,7). During May-June 2017, VDPV2 was isolated from stool specimens from two children with acute flaccid paralysis (AFP) in Deir-ez-Zor governorate, Syria. The first isolate differed from Sabin vaccine virus by 22 nucleotides in the VP1 coding region (903 nucleotides). Genetic sequence analysis linked the two cases, confirming an outbreak of circulating VDPV2 (cVDPV2). Poliovirus surveillance activities were intensified, and three rounds of vaccination campaigns, aimed at children aged <5 years, were conducted using monovalent OPV type 2 (mOPV2). During the outbreak, 74 cVDPV2 cases were identified; the most recent occurred in September 2017. Evidence indicates that enhanced surveillance measures coupled with vaccination activities using mOPV2 have interrupted cVDPV2 transmission in Syria.

Broadly neutralizing anti-influenza virus antibodies: enhancement of neutralizing potency in polyclonal mixtures and IgA backbones.

UNLABELLED: Current influenza virus vaccines rely upon the accurate prediction of circulating virus strains months in advance of the actual influenza season in order to allow time for vaccine manufacture. Unfortunately, mismatches occur frequently, and even when perfect matches are achieved, suboptimal vaccine efficacy leaves several high-risk populations vulnerable to infection. However, the recent discovery of broadly neutralizing antibodies that target the hemagglutinin (HA) stalk domain has renewed hope that the development of "universal" influenza virus vaccines may be within reach. Here, we examine the functions of influenza A virus hemagglutinin stalk-binding antibodies in an endogenous setting, i.e., as polyclonal preparations isolated from human sera. Relative to monoclonal antibodies that bind to the HA head domain, the neutralization potency of monoclonal stalk-binding antibodies was vastly inferior in vitro but was enhanced by several orders of magnitude in the polyclonal context. Furthermore, we demonstrated a surprising enhancement in IgA-mediated HA stalk neutralization relative to that achieved by antibodies of IgG isotypes. Mechanistically, this could be explained in two ways. Identical variable regions consistently neutralized virus more potently when in an IgA backbone compared to an IgG backbone. In addition, HA-specific memory B cells isolated from human peripheral blood were more likely to be stalk specific when secreting antibodies of IgA isotypes compared to those secreting IgG. Taken together, our data provide strong evidence that HA stalk-binding antibodies perform optimally when in a polyclonal context and that the targeted elicitation of HA stalk-specific IgA should be an important consideration during "universal" influenza virus vaccine design. IMPORTANCE: Influenza viruses remain one of the most worrisome global public health threats due to their capacity to cause pandemics. While seasonal vaccines fail to protect against the emergence of pandemic strains, a new class of broadly neutralizing antibodies has been recently discovered and may be the key to developing a "universal" influenza virus vaccine. While much has been learned about the biology of these antibodies, most studies have focused only on monoclonal antibodies of IgG subtypes. However, the study of monoclonal antibodies often fails to capture the complexity of antibody functions that occur during natural polyclonal responses. Here, we provide the first detailed analyses of the biological activity of these antibodies in polyclonal contexts, comparing both IgG and IgA isotypes isolated from human donors. The striking differences observed in the functional properties of broadly neutralizing antibodies in polyclonal contexts will be essential for guiding design of "universal" influenza virus vaccines and therapeutics.

Central role of conventional dendritic cells in regulation of bone marrow release and survival of neutrophils.

Neutrophils are the most abundant cell type in the immune system and play an important role in the innate immune response. Using a diverse range of mouse models with either defective dendritic cell (DC) development or conditional DC depletion, we provide in vivo evidence indicating that conventional DCs play an important role in the regulation of neutrophil homeostasis. Flk2, Flt3L, and Batf3 knockout mice, which have defects in DC development, have increased numbers of liver neutrophils in the steady state. Conversely, neutrophil frequency is reduced in DC-specific PTEN knockout mice, which have an expansion of CD8(+) and CD103(+) DCs. In chimeric CD11c-DTR mice, conventional DC depletion results in a systemic increase of neutrophils in peripheral organs in the absence of histological inflammation or an increase in proinflammatory cytokines. This effect is also present in splenectomized chimeric CD11c-DTR mice and is absent in chimeric mice with 50% normal bone marrow. In chimeric CD11c-DTR mice, diphtheria toxin treatment results in enhanced neutrophil trafficking from the bone marrow into circulation and increased neutrophil recruitment. Moreover, there is an increased expression of chemokines/cytokines involved in neutrophil homeostasis and reduced neutrophil apoptosis. These data underscore the role of the DC pool in regulating the neutrophil compartment in nonlymphoid organs.

Perfluoroalkyl substance serum concentrations and immune response to FluMist vaccination among healthy adults.

Perfluoroalkyl substances (PFAS) were shown to be immunotoxic in laboratory animals. There is some epidemiological evidence that PFAS exposure is inversely associated with vaccine-induced antibody concentration. We examined immune response to vaccination with FluMist intranasal live attenuated influenza vaccine in relation to four PFAS (perfluorooctanoate, perfluorononanoate, perfluorooctane sulfonate, perfluorohexane sulfonate) serum concentrations among 78 healthy adults vaccinated during the 2010-2011 influenza season. We measured anti-A H1N1 antibody response and cytokine and chemokine concentrations in serum pre-vaccination, 3 days post-vaccination, and 30 days post-vaccination. We measured cytokine, chemokine, and mucosal IgA concentration in nasal secretions 3 days post-vaccination and 30 days post-vaccination. Adults with higher PFAS concentrations were more likely to seroconvert after FluMist vaccination as compared to adults with lower PFAS concentrations. The associations, however, were imprecise and few participants seroconverted as measured either by hemagglutination inhibition (9%) or immunohistochemical staining (25%). We observed no readily discernable or consistent pattern between PFAS concentration and baseline cytokine, chemokine, or mucosal IgA concentration, or between PFAS concentration and change in these immune markers between baseline and FluMist-response states. The results of this study do not support a reduced immune response to FluMist vaccination among healthy adults in relation to serum PFAS concentration. Given the study's many limitations, however, it does not rule out impaired vaccine response to other vaccines or vaccine components in either children or adults.

Human cytomegalovirus modulates monocyte-mediated innate immune responses during short-term experimental latency in vitro.

UNLABELLED: The ability of human cytomegalovirus (HCMV) to establish lifelong persistence and reactivate from latency is critical to its success as a pathogen. Here we describe a short-term in vitro model representing the events surrounding HCMV latency and reactivation in circulating peripheral blood monocytes that was developed in order to study the immunological consequence of latent virus carriage. Infection of human CD14(+) monocytes by HCMV resulted in the immediate establishment of latency, as evidenced by the absence of particular lytic gene expression, the transcription of latency-associated mRNAs, and the maintenance of viral genomes. Latent HCMV induced cellular differentiation to a macrophage lineage, causing production of selective proinflammatory cytokines and myeloid-cell chemoattractants that most likely play a role in virus dissemination in the host. Analysis of global cellular gene expression revealed activation of innate immune responses and the modulation of protein and lipid synthesis to accommodate latent HCMV infection. Remarkably, monocytes harboring latent virus exhibited selective responses to secondary stimuli known to induce an antiviral state. Furthermore, when challenged with type I and II interferon, latently infected cells demonstrated a blockade of signaling at the level of STAT1 phosphorylation. The data demonstrate that HCMV reprograms specific cellular pathways in monocytes, most notably innate immune responses, which may play a role in the establishment of, maintenance of, and reactivation from latency. The modulation of innate immune responses is likely a viral evasion strategy contributing to viral dissemination and pathogenesis in the host. IMPORTANCE: HCMV has the ability to establish a lifelong infection within the host, a phenomenon termed latency. We have established a short-term model system in human peripheral blood monocytes to study the immunological relevance of latent virus carriage. Infection of CD14(+) monocytes by HCMV results in the generation of latency-specific transcripts, maintenance of viral genomes, and the capacity to reenter the lytic cycle. During short-term latency in monocytes the virus initiates a program of differentiation to inflammatory macrophages that coincides with the modulation of cytokine secretion and specific cellular processes. HCMV-infected monocytes are hindered in their capacity to exert normal immunoprotective mechanisms. Additionally, latent virus disrupts type I and II interferon signaling at the level of STAT1 phosphorylation. This in vitro model system can significantly contribute to our understanding of the molecular and inflammatory factors that initiate HCMV reactivation in the host and allow the development of strategies to eradicate virus persistence.