Efficacy, Immunogenicity, and Safety of a 9-Valent Human Papillomavirus Vaccine: Subgroup Analysis of Participants From Asian Countries.

Background: A 9-valent human papillomavirus-6/11/16/18/31/33/45/52/58 (9vHPV) vaccine extends coverage to 5 next most common oncogenic types (31/33/45/52/58) in cervical cancer versus quadrivalent HPV (qHPV) vaccine. We describe efficacy, immunogenicity, and safety in Asian participants (India, Hong Kong, South Korea, Japan, Taiwan, and Thailand) from 2 international studies: a randomized, double-blinded, qHPV vaccine-controlled efficacy study (young women aged 16-26 years; NCT00543543; Study 001); and an immunogenicity study (girls and boys aged 9-15 years; NCT00943722; Study 002). Methods: Participants (N = 2519) were vaccinated at day 1 and months 2 and 6. Gynecological samples (Study 001 only) and serum were collected for HPV DNA and antibody assessments, respectively. Injection-site and systemic adverse events (AEs) were monitored. Data were analyzed by country and vaccination group. Results: 9vHPV vaccine prevented HPV-31/33/45/52/58-related persistent infection with 90.4%-100% efficacy across included countries. At month 7, ≥97.9% of participants seroconverted for each HPV type. Injection-site AEs occurred in 77.7%-83.1% and 81.9%-87.5% of qHPV and 9vHPV vaccine recipients in Study 001, respectively, and 62.4%-85.7% of girls/boys in Study 002; most were mild to moderate. Conclusions: The 9vHPV vaccine is efficacious, immunogenic, and well tolerated in Asian participants. Data support 9vHPV vaccination programs in Asia. Clinical Trials Registration: NCT00543543; NCT00943722.

Safety profile of the 9-valent human papillomavirus vaccine: assessment in prior quadrivalent HPV vaccine recipients and in men 16 to 26 years of age.

A 9-valent HPV (9vHPV) vaccine has been developed to protect against HPV type 6/11/16/18/31/33/45/52/58-related infection and disease. Previous safety analyses from 7 clinical trials conducted in 9vHPV vaccine recipients 9-26 years of age, including comparisons of 9vHPV and quadrivalent HPV (qHPV) vaccines in girls and women 16-26 years of age, showed that the 9vHPV vaccine was generally well tolerated. Additional safety analyses were conducted to include the results of new clinical studies. The safety profile of the 9vHPV vaccine in prior qHPV vaccine recipients (n = 3756 from 1 randomized controlled trial and 2 open-label extension studies) and young men (n = 248 9vHPV and n = 248 qHPV vaccine recipients from 1 randomized controlled trial) was evaluated. Vaccine was administered as a 3-dose regimen (at Day 1 and Months 2 and 6), and adverse events (AEs) were monitored. The most common AEs were injection-site events (91.1% and 79.0% in prior qHPV vaccine recipients and young men, respectively), the majority of which were mild. Discontinuations due to an AE were rare (0.2% and 0.0% among prior qHPV vaccine recipients and young men, respectively). In young men, the AE profile of the 9vHPV vaccine was generally similar to that of the qHPV vaccine. Overall, the 9vHPV vaccine was generally well tolerated in prior qHPV vaccine recipients and in young men, with an AE profile generally consistent with that previously reported with the broader clinical program.

A coupled sensor-spectrophotometric device for continuous measurement of formaldehyde in indoor environments.

Despite long-standing awareness of adverse health effects associated with chronic human exposure to formaldehyde, this hazardous air pollutant remains a challenge to measure in indoor environments. Traditional analytical techniques evaluate formaldehyde concentrations over several hours to several days in a single location in a residence, making it difficult to characterize daily temporal and spatial variation in human exposure to formaldehyde. There is a need for portable, easy-to-use devices that are specific and sensitive to gas-phase formaldehyde over short sampling periods so that dynamic processes governing formaldehyde fate, transport, and potential remediation in indoor environments may be studied more effectively. A recently developed device couples a chemical sensor element with spectrophotometric analysis for detection and quantification of part per billion (ppbv) gas-phase formaldehyde concentrations. This study established the ability of the coupled sensor-spectrophotometric device (CSSD) to report formaldehyde concentrations accurately and continuously on a 30-min sampling cycle at low ppbv concentrations previously untested for this device in a laboratory setting. Determination of the method detection limit (MDL), based on 40 samples each at test concentrations of 5 and 10 ppbv, was found to be 1.9 and 2.0 ppbv, respectively. Performance of the CSSD was compared with the dinitrophenylhydrazine (DNPH) derivatization method for formaldehyde concentrations ranging from 5-50 ppbv, and a linear relationship with a coefficient of determination of 0.983 was found between these two analytical techniques. The CSSD was also used to monitor indoor formaldehyde concentrations in two manufactured homes. During this time, formaldehyde concentrations varied from below detection limit to 65 ppbv and were above the US National Institute for Occupational Safety and Health (NIOSH) recommended exposure limit (REL) of 16 ppbv, which is also the exposure limit value now adopted by the US Federal Emergency Management Agency (FEMA) to procure manufactured housing, 80% and 100% of the time, respectively.

Proteomic analysis of the supernatant of red blood cell units: the effects of storage and leucoreduction.

BACKGROUND: Red blood cell (RBC) transfusion is a life-saving intervention for critically ill patients; however, it has been linked to increased morbidity and mortality. We hypothesize that a number of important proteins accumulate during routine storage of RBCs, which may explain some of the adverse effects seen in transfused patients. STUDY DESIGN: Five RBC units were drawn and divided (half prestorage leucoreduced (LR-RBC) and half left as an unmodified control (RBC). The supernatant was separated on days 1 and 42 of storage and proteomic analyses completed with in-gel tryptic digestion and nano-liquid chromatography tandem mass spectrometry. RESULTS: In RBC supernatants, 401 proteins were identified: 203 increased with storage, 114 decreased, and 84 were unchanged. In LR-RBC supernatant, 231 proteins were identified: 84 increased with storage, 30 decreased, and 117 were unchanged. Prestorage leucoreduction removed many platelet- and leucocyte-derived structural proteins; however, a number of intracellular proteins accumulated including peroxiredoxins (Prdx) 6 and latexin. The increases were confirmed by immunoblotting, including the T-phosphorylation of Prdx-6, indicating that it may be functioning as an active phospholipase. Active matrix metalloproteinase-9 also increased with a coinciding decrease in the metalloproteinase inhibitor 1 and cystatin C. CONCLUSION: We conclude that a number of proteins increase with RBC storage, which is partially ameliorated with leucoreduction, and transfusion of stored RBCs may introduce mediators that result in adverse events in the transfused host.

Human papillomavirus related head and neck cancer survival: a systematic review and meta-analysis.

Human Papillomavirus (HPV) related oropharyngeal squamous cell carcinomas (OPSCCs) are reported to have improved prognosis and survival in comparison to other head and neck squamous cell cancers (HNSCCs). This systematic review and meta-analysis examines survival differences in HPV-positive HNSCC and OPSCC subtypes including tonsillar carcinoma in studies not previously investigated. Four electronic databases were searched from their inception till April 2011. A random effects meta-analysis was used to pool study estimates evaluating disease-specific (death from HNSCC), overall (all-cause mortality), progression-free and disease-free (recurrence free) survival outcomes in HPV-positive vs. HPV-negative HNSCCs. All statistical tests were two-sided. Forty-two studies were included. Patients with HPV-positive HNSCC had a 54% better overall survival compared to HPV-negative patients HR 0.46 (95% CI 0.37-0.57); the pooled HR for tonsillar cancer and OPSCC was 0.50 (95% CI 0.33-0.77) and HR 0.47 (95% CI 0.35-0.62) respectively. The pooled HR for disease specific survival was 0.28 (95% CI 0.19-0.40); similar effect sizes were found irrespective of the adjustment for confounders, HPV detection methods or study location. Both progression-free survival and disease-free survival were significantly improved in HPV-positive HNSCCs. HPV-positive HNSCCs and OPSCCs patients have a significantly lower disease specific mortality and are less likely to experience progression or recurrence of their cancer than HPV-negative patients; findings which have connotations for treatment selection in these patients.

Diagnosis and surgical treatment of an intracranial cyst in an alpaca cria.

CASE DESCRIPTION: A 7-day-old female alpaca was examined because of an acute onset of diffuse central neurologic deficits. CLINICAL FINDINGS: Diagnostic imaging with CT and MRI identified an intracranial cyst occupying approximately one-third to one-half of the dorsal portion of the cranial cavity, markedly displacing the cerebral hemispheres bilaterally. TREATMENT AND OUTCOME: Initial surgical management via trephination and needle drainage was only transiently effective at resolving the neurologic signs. Craniotomy and drainage and removal of the cyst lining resulted in a sustained improvement in neurologic status, and the cria remained clinically normal and well grown at follow-up 5 months after surgery. CLINICAL RELEVANCE: This report represented the first description of the successful treatment of an intracranial cyst in a New World camelid.

Gas-phase formaldehyde adsorption isotherm studies on activated carbon: correlations of adsorption capacity to surface functional group density.

Formaldehyde (HCHO) adsorption isotherms were developed for the first time on three activated carbons representing one activated carbon fiber (ACF) cloth, one all-purpose granular activated carbon (GAC), and one GAC commercially promoted for gas-phase HCHO removal. The three activated carbons were evaluated for HCHO removal in the low-ppm(v) range and for water vapor adsorption from relative pressures of 0.1-0.9 at 26 °C where, according to the IUPAC isotherm classification system, the adsorption isotherms observed exhibited Type V behavior. A Type V adsorption isotherm model recently proposed by Qi and LeVan (Q-L) was selected to model the observed adsorption behavior because it reduces to a finite, nonzero limit at low partial pressures and it describes the entire range of adsorption considered in this study. The Q-L model was applied to a polar organic adsorbate to fit HCHO adsorption isotherms for the three activated carbons. The physical and chemical characteristics of the activated carbon surfaces were characterized using nitrogen adsorption isotherms, X-ray photoelectron spectroscopy (XPS), and Boehm titrations. At low concentrations, HCHO adsorption capacity was most strongly related to the density of basic surface functional groups (SFGs), while water vapor adsorption was most strongly influenced by the density of acidic SFGs.

Effect of vessel size on the flow efficiency of the total cavopulmonary connection: in vitro studies.

The total cavopulmonary connection (TCPC) creates a passive system of blood flow into the pulmonary circulation. We hypothesize that the efficiency differences found in models with superior vena cava-inferior vena cava (SVC-IVC) offsets is dependent on vessel size, with flow efficiency improving with larger size vessels. Two sets of in vitro TCPC models (TCPC-3 and TCPC-15) were constructed corresponding to average vessel diameters of 3- and 15-year-old patients. The model with full SVC-IVC offset was the most efficient in TCPC-3 models. There was no significant difference between geometric arrangements in TCPC-15 models; however, the average efficiencies were significantly higher. Among the models representing vessel sizes of the younger age group, the model with the full-diameter SVC-IVC offset was the most efficient. The models representing vessel sizes of the older age group showed marked improvement in efficiencies throughout without obvious differences between various geometric arrangements. This suggests that geometric considerations in TCPC surgical techniques may be of lower than expected significance over the life span of a patient. More important, after balancing the effects of improved flow efficiency with larger vessels against the effects of chronic volume overload, the trend of performing the Fontan surgery on increasingly younger patients may need to be reconsidered after further studies.

Inflammatory mediators in patients receiving long-term home parenteral nutrition.

This study was designed to examine circulating and urine cytokine levels in patients receiving long-term home total parenteral nutrition (TPN) support. Twelve patients who had been receiving home TPN for more than 1 year (range, 1.3-19.5 years) were enrolled for study. To avoid the potential confounding effects of intercurrent infection, patients were studied during periods of clinical stability without clinical evidence of infection. Ten normal healthy volunteers served as controls. Serum levels of albumin and C-reactive protein, temperature, body weight, and blood white cell counts were determined. The levels of soluble tumor necrosis factor receptor II (sTNF-RII) and interleukin 6 (IL-6) were measured in serum and 24-hr urine. The results showed that the concentrations of sTNF-RII and IL-6 in 24-hr urine and serum were significantly higher in patients, indicating that long-term home TPN may be associated with a persistent low-grade inflammatory state.

Noncovalent interaction between ubiquitin and the human DNA repair protein Mms2 is required for Ubc13-mediated polyubiquitination.

Ubiquitin-conjugating enzyme variants share significant sequence similarity with typical E2 (ubiquitin-conjugating) enzymes of the protein ubiquitination pathway but lack their characteristic active site cysteine residue. The MMS2 gene of Saccharomyces cerevisiae encodes one such ubiquitin-conjugating enzyme variant that is involved in the error-free DNA postreplicative repair pathway through its association with Ubc13, an E2. The Mms2-Ubc13 heterodimer is capable of linking ubiquitin molecules to one another through an isopeptide bond between the C terminus and Lys-63. Using highly purified components, we show here that the human forms of Mms2 and Ubc13 associate into a heterodimer that is stable over a range of conditions. The ubiquitin-thiol ester form of the heterodimer can be produced by the direct activation of its Ubc13 subunit with E1 (ubiquitin-activating enzyme) or by the association of Mms2 with the Ubc13-ubiquitin thiol ester. The activated heterodimer is capable of transferring its covalently bound ubiquitin to Lys-63 of an untethered ubiquitin molecule, resulting in diubiquitin as the predominant species. In (1)H (15)N HSQC ((1)H (15)N heteronuclear single quantum coherence) NMR experiments, we have mapped the surface determinants of tethered and untethered ubiquitin that interact with Mms2 and Ubc13 in both their monomeric and dimeric forms. These results have identified a surface of untethered ubiquitin that interacts with Mms2 in the monomeric and heterodimeric form. Furthermore, the C-terminal tail of ubiquitin does not participate in this interaction. These results suggest that the role of Mms2 is to correctly orient either a target-bound or untethered ubiquitin molecule such that its Lys-63 is placed proximally to the C terminus of the ubiquitin molecule that is linked to the active site of Ubc13.

Crystal structure of the human ubiquitin conjugating enzyme complex, hMms2-hUbc13.

The ubiquitin conjugating enzyme complex Mms2-Ubc13 plays a key role in post-replicative DNA repair in yeast and the NF-kappaB signal transduction pathway in humans. This complex assembles novel polyubiquitin chains onto yet uncharacterized protein targets. Here we report the crystal structure of a complex between hMms2 (Uev1) and hUbc13 at 1.85 A resolution and a structure of free hMms2 at 1.9 A resolution. These structures reveal that the hMms2 monomer undergoes a localized conformational change upon interaction with hUbc13. The nature of the interface provides a physical basis for the preference of Mms2 for Ubc13 as a partner over a variety of other structurally similar ubiquitin-conjugating enzymes. The structure of the hMms2-hUbc13 complex provides the conceptual foundation for understanding the mechanism of Lys 63 multiubiquitin chain assembly and for its interactions with the RING finger proteins Rad5 and Traf6.

Unexpected nitrosyl-group bending in six-coordinate [M(NO)](6) sigma-bonded aryl(iron) and -(ruthenium) porphyrins.

The six-coordinate nitrosyl sigma-bonded aryl(iron) and -(ruthenium) porphyrin complexes (OEP)Fe(NO)(p-C(6)H(4)F) and (OEP)Ru(NO)(p-C(6)H(4)F) (OEP = octaethylporphyrinato dianion) have been synthesized and characterized. Single-crystal X-ray structure determinations reveal an unprecedented bending and tilting of the MNO group for both [MNO](6) species as well as significant lengthening of trans axial bond distances. In (OEP)Fe(NO)(p-C(6)H(4)F) the Fe-N-O angle is 157.4(2) degrees, the nitrosyl nitrogen atom is tilted off of the normal to the heme plane by 9.2 degrees, Fe-N(NO) = 1.728(2) A, and Fe-C(aryl) = 2.040(3) A. In (OEP)Ru(NO)(p-C(6)H(4)F) the Ru-N-O angle is 154.9(3) degrees, the nitrosyl nitrogen atom is tilted off of the heme normal by 10.8 degrees, Ru-N(NO) = 1.807(3) A, and Ru-C(aryl) = 2.111(3) A. We show that these structural features are intrinsic to the molecules and are imposed by the strongly sigma-donating aryl ligand trans to the nitrosyl. Density functional-based calculations reproduce the structural distortions observed in the parent (OEP)Fe(NO)(p-C(6)H(4)F) and, combined with the results of extended Hückel calculations, show that the observed bending and tilting of the FeNO group indeed represent a low-energy conformation. We have identified specific orbital interactions that favor the unexpected bending and tilting of the FeNO group. The aryl ligand also affects the Fe-NO pi-bonding as measured by infrared and (57)Fe Mössbauer spectroscopies. The solid-state nitrosyl stretching frequencies for the iron complex (1791 cm(-)(1)) and the ruthenium complex (1773 cm(-)(1)) are significantly reduced compared to their respective [MNO](6) counterparts. The Mössbauer data for (OEP)Fe(NO)(p-C(6)H(4)F) yield the quadrupole splitting parameter +0.57 mm/s and the isomer shift 0.14 mm/s at 4.2 K. The results of our study show, for the first time, that bent Fe-N-O linkages are possible in formally ferric nitrosyl porphyrins.

Functional production of mammalian concentrative nucleoside transporters in Saccharomyces cerevisiae.

The transport of nucleosides and nucleobases in the yeast Saccharomyces cerevisiae is reviewed and the use of this organism to study recombinant mammalian concentrative nucleoside transport (CNT) proteins is described. A selection strategy based on the ability of an expressed nucleoside transporter cDNA to mediate thymidine uptake by yeast under a selective condition that depletes endogenous thymidylate was used to assess the transport capacity of heterologous transporter proteins. The pyrimidine-nucleoside selective concentrative transporters from human (hCNT1) and rat (rCNT1) complemented the imposed thymidylate depletion in S. cerevisiae, as did N-terminally truncated versions of hCNT1 and rCNT1 lacking up to 31 amino acids. Transporter-mediated rescue of S. cerevisiae by both nucleoside transporters was inhibited by cytidine, uridine and adenosine, but not by guanosine or inosine. This work represents the development of a new model system for the functional production of recombinant nucleoside transporters of the CNT family of membrane proteins.

Structural and electronic characterization of nitrosyl(octaethylporphinato)iron(III) perchlorate derivatives.

The synthesis and crystallographic characterization of the five-coordinate iron(III) porphyrinate complex [Fe(OEP)(NO)]ClO4 are reported. This [FeNO]6 complex has a nearly linear Fe-N-O group (angle = 173.19(13) degrees) with a small off-axis tilt of the Fe-N(NO) vector from the heme normal (angle = 4.6 degrees); the Fe-N(NO) distance is 1.6528(13) A and the iron is displaced 0.32 A out-of-plane. The complex forms a tight cofacial pi-pi dimer in the solid state. Mössbauer spectra for this derivative as well as for a related crystalline form are measured both in zero applied magnetic field and in a 7 T applied field. Fits to the measurements made in applied magnetic field demonstrate that both crystalline forms of [Fe(OEP)(NO)]ClO4 have a diamagnetic ground state at 4.2 K. The observed isomer shifts (delta = 0.22-0.24 mm/s) are smaller than those typically observed for low-spin iron(III) porphyrinates. Analogous Mössbauer measurements are also obtained for a six-coordinate derivative, [Fe(OEP)(Iz)(NO)]ClO4 (Iz = indazole). The observed isomer shift for this species is smaller still (delta = 0.02 mm/s). All derivatives show a strong temperature dependence of the isomer shift. The data emphasize the strongly covalent nature of the FeNO group. The Mössbauer isomer shifts suggest formal oxidation states greater than +3 for iron, but the NO stretching frequencies are not consistent with such a large charge transfer to NO. Differences in the observed nitrosyl stretching frequencies of the two crystalline forms of [Fe(OEP)(NO)]ClO4 are discussed.

Postinfection purpura fulminans in a patient heterozygous for prothrombin G20210A and acquired protein S resistance.

Purpura fulminans usually consists of large, often symmetrical, spreading ecchymosis, which may later develop into extensive areas of skin necrosis and peripheral gangrene. Postinfectious purpura fulminans associated with an autoantibody directed against protein S has been described. The interaction and the contribution of recently described mutations such as factor V Leiden and prothrombin G20210A to the development and progression of postinfectious purpura fulminans and venous thrombosis is not known. The authors describe a patient heterozygous for prothrombin G20210A who developed purpura fulminans and extensive venous thrombosis secondary to acquired protein S deficiency.

Screening for cancers of the head and neck: addressing the problem.

More than 90% of upper aerodigestive tract (UADT) cancers occur in people with specific lifestyle risks, including tobacco and alcohol use. More than 90% of tumors occur in easily examined parts of the head and neck, therefore, there is the possibility of identifying the vast majority of patients through selective screening. Physicians should keep in mind that the mucosa's sojourn from visually suspicious (and possibly malignant) tissue is most likely less than two years, and frequent examination of asymptomatic patients is necessary. When patients wait to bring symptoms to medical attention, their cancers will be advanced 60% of the time when the chance of cure is less than 30%. Given the difficulty of implementing regular examinations in a poorly compliant, high risk population, genetic and molecular screening tools may allow very high risk individuals to be identified.

Incidence, prognosis, and etiology of end-stage liver disease in patients receiving home total parenteral nutrition.

BACKGROUND: Elevations in liver function tests have been reported in patients receiving total parenteral nutrition (TPN). The clinical aspects of end-stage liver disease (ESLD) associated with the prolonged use of home TPN have not been fully clarified. In previous series patients with duodenocolostomies appeared to be at higher risk than persons with some jejunum or ileum remaining in situ. METHODS: The records of 42 patients treated with home TPN for more than 1 year were examined. This constituted 283 person-years of home TPN. Patients with duodenocolostomies were examined as a separate group on the basis of the literature experience. RESULTS: Six of 42 patients who received chronic home TPN had ESLD with 100% subsequent mortality, at an average of 10.8 +/- 7.1 months after the initial bilirubin elevation. Thirteen of 42 patients had superior mesenteric artery or vein thrombosis (SMT) leading to duodenocolostomy. In 8 of these 13 patients with SMT and underlying inflammatory or malignant disorder, 2 had ESLD. The remaining 5 SMT patients who had only minimal liver enzyme elevation over 13.6 +/- 6.7 (range 3 to 19) years of home TPN were significantly younger (36 +/- 7 years vs 64 +/- 13 years) and did not have underlying inflammation either by clinical diagnosis or as reflected in the high normal serum albumin level (> or = 4.0 g/dL). Despite their extreme short bowel syndrome and long exposure to home TPN, ESLD did not develop. CONCLUSIONS: Approximately 15% of patients who receive prolonged TPN have ESLD with a high rate of morbidity and mortality. The combination of chronic inflammation and the short bowel syndrome appears to be necessary for the development of ESLD with prolonged home TPN.

Avoidance of primary post-tonsillectomy hemorrhage in a teaching program.

OBJECTIVE: To determine the incidence of primary post-tonsillectomy hemorrhage in a teaching institution by using a uniform technique, including a 3-minute relaxation of retraction before case termination and the use of bismuth subgallate. DESIGN: Case series. SETTING: Tertiary care academic pediatric center. PATIENTS: A 7-year retrospective study was performed by using the medical records of 1286 children without a bleeding abnormality who underwent tonsillectomy (with or without adenoidectomy). A uniform technique, proposed to reduce hemorrhage, was used for 705 children and was not used for 581 children. RESULTS: No episodes of primary hemorrhage (onset < or = 24 hours after surgery) occurred, and the incidence of delayed hemorrhage (onset >24 hours after surgery) was 1.1% in the study group. The primary hemorrhage rate of the study group was significantly lower (P = .007) than the rate for the reference group (0.0% vs 1.0%), as was the total hemorrhage rate (1.1% vs 4.1%) and the delayed hemorrhage rate (1.1% vs 3.1%). CONCLUSION: A uniform technique including the use of bismuth subgallate and reassessment of the tonsillar fossae after a 3-minute observation period reduces the incidence of primary tonsillar hemorrhage in a teaching institution setting.

Report of the first case of invasive fungal sinusitis caused by Scopulariopsis acremonium: review of scopulariopsis infections.

Scopulariopsis acremonium is a species of saprophytic fungus not previously reported to cause invasive disease in humans, although invasive infections from other species of Scopulariopsis have been reported and are reviewed. Deep infection with this fungus is associated with a high mortality rate. Invasive fungal sinusitis, in general, is a potentially fatal disease that typically affects immunocompromised patients, such as those receiving intensive chemotherapy or undergoing bone marrow transplantation. We report a case of invasive fungal sinusitis caused by Scopulariopsis acremonium in a patient with leukemia, who was successfully treated with amphotericin B, itraconazole, endoscopic sinus surgery, and granulocyte colony-stimulating factor.