Bias correction methods for test-negative designs in the presence of misclassification.

The test-negative design (TND) has become a standard approach for vaccine effectiveness (VE) studies. However, previous studies suggested that it may be more vulnerable than other designs to misclassification of disease outcome caused by imperfect diagnostic tests. This could be a particular limitation in VE studies where simple tests (e.g. rapid influenza diagnostic tests) are used for logistical convenience. To address this issue, we derived a mathematical representation of the TND with imperfect tests, then developed a bias correction framework for possible misclassification. TND studies usually include multiple covariates other than vaccine history to adjust for potential confounders; our methods can also address multivariate analyses and be easily coupled with existing estimation tools. We validated the performance of these methods using simulations of common scenarios for vaccine efficacy and were able to obtain unbiased estimates in a variety of parameter settings.

Two γ-ray bursts from dusty regions with little molecular gas.

Long-duration γ-ray bursts are associated with the explosions of massive stars and are accordingly expected to reside in star-forming regions with molecular gas (the fuel for star formation). Previous searches for carbon monoxide (CO), a tracer of molecular gas, in burst host galaxies did not detect any emission. Molecules have been detected as absorption in the spectra of γ-ray burst afterglows, and the molecular gas is similar to the translucent or diffuse molecular clouds of the Milky Way. Absorption lines probe the interstellar medium only along the line of sight, so it is not clear whether the molecular gas represents the general properties of the regions where the bursts occur. Here we report spatially resolved observations of CO line emission and millimetre-wavelength continuum emission in two galaxies hosting γ-ray bursts. The bursts happened in regions rich in dust, but not particularly rich in molecular gas. The ratio of molecular gas to dust (<9-14) is significantly lower than in star-forming regions of the Milky Way and nearby star-forming galaxies, suggesting that much of the dense gas where stars form has been dissipated by other massive stars.

Histamine-2 receptor antagonists (H2RA) may negatively impact ADL assessment in patients on a convalescent rehabilitation ward.

Background/aim: In the convalescent rehabilitation ward, many elderly patients undergo rehabilitation. Histamine-2 receptor antagonists (H2RA), which is a one of the acid secretion inhibitors, is frequently prescribed for the patients as a peptic ulcer prevention measure. At present, H2RA are reported as being associated with factors that reduce cognitive function. However, little is known about the relationship H2RA and rehabilitation outcome. Therefore, this study examined the relationship between H2RA use and Functional Independence Measure (FIM) gain, which determines rehabilitation outcomes for patients admitted to the convalescent rehabilitation ward. Patients and methods: We retrospectively investigated FIM gain on discharge by both the administration group (H2RA (+)) (n = 118) and non-administration group (H2RA (-)) (n = 118). Results: The FIM gain scores of Motor FIM total, Cognition FIM total, and Total FIM were significantly lower in H2RA (+) than in H2RA (-) (Motor FIM total: 8.0 [4.0-16.0] [Inter-Quartile Range] vs. 12.0 [5.0-19.2], p =0.0217, Cognition FIM total: 3.0 [1.0-6.0] vs. 5.0 [2.0-7.0], p =0.0120, Total FIM: 11.5 [4.8-20.2] vs. 17.0 [8.0-27.0], p =0.0089). Conclusion: The administration of H2RA to elderly patients undergoing rehabilitation may prevent cognitive function maintenance or recovery by rehabilitation.

Differentiation between Bacillus amyloliquefaciens and Bacillus subtilis isolated from a South African sugarcane processing factory using ARDRA and rpoB gene sequencing.

A total of 104 exopolysaccharide (gum)-producing bacteria were isolated from the juice screen and juice tank in a sugarcane processing factory at times of low- and high dextran concentrations in the produced sugar. Dextran is an indicator of cane deterioration and sucrose loss after harvesting of the cane. The isolates were identified as Bacillus amyloliquefaciens (96 isolates) and Bacillus subtilis (eight isolates) based on restriction enzyme banding patterns of amplified 16S rRNA genes and rpoB gene sequence analysis. Exopolysaccharide production in sugarcane is normally associated with dextran produced by Leuconostoc mesenteroides. B. amyloliquefaciens, and to a lesser extent B. subtilis, could, however, also be responsible for exopolysaccharide (slime or gum) production in cane processing factories.

Outcomes of patients receiving a massive transfusion for major trauma.

BACKGROUND: The benefits of high transfusion ratios (plasma to red blood cells and platelets to red blood cells) on survival in injured patients who receive massive transfusions remain uncertain. This study aimed to assess the association between transfusion ratios and adverse events and survival in patients undergoing massive transfusion for major trauma. METHODS: A retrospective observational study was conducted on patients who had major trauma using a Japanese national administrative database. The associations between transfusion ratios and outcomes (in-hospital mortality and incidence of adverse events) were analysed using a non-linear logistic generalized additive model (GAM). In a logistic generalized estimating equation model, adjusted for patient and hospital-level confounders, transfusion ratios were included as continuous or categorical variables (low, transfusion ratio 0·75 or less; intermediate, over 0·75 to 1·25; high, over 1·25). RESULTS: Some 1777 patients were included in the analysis, of whom 602 died in hospital. GAM plots of the transfusion ratios for in-hospital mortality demonstrated a downward convex unimodal curve. In-hospital mortality was similar with increasing transfusion ratios for plasma (adjusted odds ratio (OR) 1·13, 95 per cent c.i. 0·82 to 1·55; P = 0·446) and platelets (adjusted OR 0·84, 0·66 to 1·08; P = 0·171). Both plasma to red blood cell ratio (adjusted OR 1·77, 1·32 to 2·37; P < 0·001) and platelet to red blood cell ratio (adjusted OR 1·71, 1·35 to 2·15; P < 0·001) were significantly associated with a higher incidence of adverse events. No significant differences in in-hospital mortality were observed between the three transfusion categories (low, medium and high). CONCLUSION: In this study, transfusion strategies with high plasma to red blood cell and platelet to red blood cell ratios did not have survival benefits, but were associated with an increase in adverse events.

Cryogenically-cooled Yb:YGAG ceramic mode-locked laser.

This work reports on a liquid-nitrogen-cooled, SESAM mode-locked Yb:YGAG (Yb:Y(3)Ga(2)Al(3)O(12)) ceramic laser. The Yb:YGAG has a similar structure to Yb:YAG, but its emission spectrum at low temperature remains much broader, which is suitable for ultrashort pulse generation and amplification. A stable pulse train with 119-MHz repetition rate was obtained at a wavelength of 1026 nm. The measured pulse duration is 2.4 ps, which is more than four times shorter than that achieved with a cryogenically-cooled Yb:YAG. Furthermore, laser performance of the Yb:YGAG ceramics in continuous-wave operation and wavelength tunability at 80 K was investigated.

CO2 adsorption-desorption performance of mesoporous zirconium hydroxide with robust water durability.

The present study demonstrates for the first time, the development of mesoporous zirconium hydroxide with high CO2 capacity and sustainable adsorption-desorption performance within a broad range of pressures (100-3000 kPa). Mesoporous zirconium hydroxide with a high surface area of ∼400 m(2) g(-1) was prepared by a simple and easy-to-handle precipitation route. The prepared high surface area mesoporous zirconium hydroxide exhibited significantly higher CO2 adsorption uptake and working adsorption capacity on a volumetric basis within a wide range of operating pressures of 100-3000 kPa than commercially available zeolite 13X. Reversible CO2 desorption was easily achieved by a pressure swing at moderate temperatures (298.15 K). Additionally, the prepared mesoporous zirconium hydroxide was adequately stable and strong to effectuate CO2 capture over multiple adsorption-desorption cycles without major reductions in its CO2 adsorption capacity. Furthermore, the effect of co-adsorbed water on the CO2 adsorption properties of mesoporous zirconium hydroxide was investigated. In the presence of co-adsorbed water, mesoporous zirconium hydroxide displayed reversible CO2 adsorption-desorption behavior in contrast to zeolite 13X that exhibited negligible CO2 adsorption within the wide range of pressures examined. The present study demonstrates the potential of high surface area mesoporous zirconium hydroxide toward efficient CO2 capturing processes.

Elevated receptor for activated C kinase 1 expression is involved in intracellular Ca2+ influx and potentially associated with compromised regulatory T cell function in patients with asthma.

BACKGROUND: Regulatory T cells (T(regs)) are activated during anergy in response to T cell receptor (TCR) activation and functional immune suppression. Anergy of paediatric T(regs) is partially dependent on intracellular calcium mobility; following TCR activation, T(regs) do not exhibit increased intracellular Ca(2+) concentration ([Ca(2+) ](i)). OBJECTIVE: We determined whether [Ca(2+) ](i) in adult T(regs) defined their anergy, if intracellular Ca(2+) movement was linked to regulatory functions, whether [Ca(2+)](i) was indicative of asthma pathology, and the potential molecular mechanism responsible for Ca(2+) movement in T(regs). METHODS: T(regs) were purified by the magnetic bead method, and their regulatory functions were assessed by monitoring carboxyfluorescein succinimidyl ester-labelled responder T cell proliferation. The Ca(2+) response of Fura-2-labelled cells was measured using a video image analysis system. To analyse the functions of T(regs) at the molecular level, we generated Jurkat Tet-On(®) clones with doxycycline (Dox)-induced forkhead box P3 (FOXP3) protein expression. RESULTS: CD4(+) CD25(+) CD127(-/low) T(regs) from participants without asthma did not elicit Ca(2+) influx in response to TCR activation, exhibited little proliferation and suppressed proliferation of CD4(+) CD25(-) T cells. In contrast, under similar conditions, T(regs) from patients with asthma exhibited increased [Ca(2+)](i) and robust proliferation with partial loss of regulatory functions. FOXP3 protein levels in Tet-On(®) clones were high after both 2- and 5-day Dox treatment; however, 5-day cells were comparable with T(regs) from patients with asthma, whereas 2-day cells were similar to T(regs) from participants without asthma. Increasing [Ca(2+)](i) induced a high level of receptor for activated C kinase 1 (RACK1) expression in 5-day cells. CONCLUSIONS AND CLINICAL RELEVANCE: We confirmed that T(regs) in patients with asthma are functionally impaired and that the abnormal regulatory functions of these cells can be analysed by [Ca(2+)](i) following TCR engagement. Furthermore, the impaired functioning of T(regs) evident in patients with asthma may be due to a high level of RACK1.

The pharmacokinetics and safety profiles of belimumab after single subcutaneous and intravenous doses in healthy Japanese volunteers.

WHAT IS KNOWN AND OBJECTIVES: Belimumab is a recombinant human monoclonal antibody that binds and antagonizes the biological activity of soluble B-lymphocyte stimulator (BLyS) protein. BLyS appears to play a role in the pathogenesis of systemic lupus erythematosus, and the biological profile of belimumab suggests that it may have a therapeutic benefit in the treatment for the disease. In this healthy Japanese subjects study, we investigated the pharmacokinetics and safety of a single subcutaneous and intravenous injection of belimumab administered as a 200 mg/mL liquid formulation. METHODS: This was an open-label, randomized, parallel-group, single-dose study in healthy Japanese subjects. Each subject received a single intravenous infusion or a subcutaneous injection of 200 mg belimumab. The pharmacokinetic parameters and safety parameters including local tolerance (injection site), biomarkers, immunogenicity and adverse events were evaluated up to 70 days post-dosing. RESULTS: After a single intravenous or a subcutaneous administration of 200 mg belimumab, all 16 subjects completed the study. There were no serious adverse events or adverse events related to injection site reactions. All seven adverse events were considered mild or moderate in intensity and deemed unrelated to belimumab except for cellulitis following intravenous administration. The bioavailability of the single subcutaneous dose of 200 mg belimumab in the subjects was estimated to be 77·5%. Time to the maximum serum concentration after subcutaneous injection was 6·5 days (median). The geometric mean terminal half-life was comparable between the two administration routes (17·7 days intravenous and 15·9 days subcutaneous). Serum immunoglobulin G level decreased slightly after each treatment. No subjects were found to produce antibelimumab antibodies. WHAT IS NEW AND CONCLUSIONS: A favourable absolute bioavailability in healthy Japanese subjects was seen following a subcutaneous injection of 200 mg belimumab. Considering the intersubject variability, exposures were consistent with those previously observed in healthy non-Japanese subjects. Safety and biomarker data were also consistent with previous non-Japanese clinical studies.

The effect of growth media and physical treatments on the adhesion properties of canine probiotics.

AIMS: The manufacturing processes have been reported to influence the properties of probiotics with potential impact on health properties. The aim was to investigate the effect of different growth media and inactivation methods on the properties of canine-originated probiotic bacteria alone and in combination mixture. METHODS AND RESULTS: Three established dog probiotics, Lactobacillus fermentum VET9A, Lactobacillus plantarum VET14A and Lactobacillus rhamnosus VET16A, and their combination mixture were evaluated for their adhesion to dog mucus. The effect of different growth media, one reflecting laboratory and the other manufacturing conditions, and inactivation methods (95°C, 80°C and UV irradiation) on the mucus adhesion of the probiotic strains was characterized. Evaluation of dog probiotics was supported by cell visualization using transmission electron microscopy (TEM). Higher adhesion percentage was reported for probiotic strains growing in laboratory rather than in manufacturing conditions (P < 0.05). Inactivation by heat (95°C, 80°C) decreased the adhesion properties when strains were cultivated in soy-based growth media compared with those grown in MRS broth (P < 0.05). TEM observations uncovered differences in cell-surface components in nonviable forms of probiotic strains as compared with their viable forms. CONCLUSIONS: Manufacturing process conditions such as growth media and pretreatment methods may significantly affect the adhesive ability of the tested strains. SIGNIFICANCE AND IMPACT OF THE STUDY: Growth conditions, growth media, pretreatment methods and different probiotic combinations should be carefully considered for quality control of existing probiotics and for identification of new probiotics for dogs. These may also have an impact on health benefits for the host.

Are fructophilic lactic acid bacteria (FLAB) beneficial to humans?

Fructophilic lactic acid bacteria (FLAB) are heterofermentative and related to the genera Fructilactobacillus, Convivina, Leuconostoc, Oenococcus and Weissella. Although they generally prefer fructose above glucose, obligate heterofermentative species will ferment glucose in the presence of external electron acceptors such as pyruvate and fructose. Little is known about the presence of FLAB in the human gut, let alone probiotic properties. In this review we discuss the possible role FLAB may have in the human gastro-intestinal tract (GIT) and highlight the advantages and disadvantages these bacteria may have in individuals with a diet high in fructose.

Deshima 2.0: Rapid Redshift Surveys and Multi-line Spectroscopy of Dusty Galaxies.

We present a feasibility study for the high-redshift galaxy part of the Science Verification Campaign with the 220-440 GHz deshima 2.0 integrated superconducting spectrometer on the ASTE telescope. The first version of the deshima 2.0 chip has been recently manufactured and tested in the lab. Based on these realistic performance measurements, we evaluate potential target samples and prospects for detecting the [CII] and CO emission lines. The planned observations comprise two distinct, but complementary objectives: (1) acquiring spectroscopic redshifts for dusty galaxies selected in far-infrared/mm-wave surveys; (2) multi-line observations to infer physical conditions in dusty galaxies.

Number fluctuations of sparse quasiparticles in a superconductor.

We have directly measured quasiparticle number fluctuations in a thin film superconducting Al resonator in thermal equilibrium. The spectrum of these fluctuations provides a measure of both the density and the lifetime of the quasiparticles. We observe that the quasiparticle density decreases exponentially with decreasing temperature, as theoretically predicted, but saturates below 160 mK to 25-55/µm(3). We show that this saturation is consistent with the measured saturation in the quasiparticle lifetime, which also explains similar observations in qubit decoherence times.

Influence of carbohydrates on the isolation of lactic acid bacteria.

AIMS: To determine the influence of carbohydrates on enrichment isolation of lactic acid bacteria from different niches. METHODS AND RESULTS: Lactic acid bacteria in three traditional fermented products in southern Africa (amasi, mahewu and tshwala) and in three fresh samples (two flowers and a fruit) were enrichment cultured in media supplemented with 13 different carbohydrates. Diversity of lactic acid bacteria was determined by PCR-denaturing-gradient gel electrophoresis. Carbohydrates used in enrichment media had a big impact on the isolation of lactic acid bacteria from fermented products. Depending on the carbohydrates tested, the number of species detected ranged from one to four in amasi, one to five in mahewu and one to three in tshwala. Fructose and mannitol selected for relatively higher numbers of lactic acid bacteria in fermented products. Specific relationships between substrates and lactic acid bacteria have been noted. On the other hand, small influences were found among carbohydrates tested in flowers and fruit. CONCLUSION: Carbohydrates have a big impact on the isolation of a variety of lactic acid bacteria in fermented food. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first study that reports the influence of carbohydrates on the enrichment of lactic acid bacteria.

Nisin F, intraperitoneally injected, may have a stabilizing effect on the bacterial population in the gastro-intestinal tract, as determined in a preliminary study with mice as model.

AIMS: To determine if nisin F has an effect on the bacterial population in the gastro-intestinal tract. METHODS AND RESULTS: Six male C57BL/6 mice were intraperitoneally injected with 200 µl sterile saline and six with nisin F (200 µl, equivalent to 640 arbitrary units). Fecal samples were collected before injection and 8, 24 and 48 h after injection, and the bacteria amplified by PCR-DGGE using 16S rDNA primers. The composition of the bacterial population in the gastro-intestinal tract (GIT) of mice that were injected with saline changed during 48 h, whereas the bacterial population in the GIT remained relatively unchanged in animals injected with nisin F. CONCLUSIONS: These results suggest that nisin F inhibits the growth of specific bacteria in the GIT within the first 4 h. Furthermore, the species remained repressed for at least 44 h after one intraperitoneal injection with nisin F. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report suggesting that nisin F may have a stabilizing effect on the bacterial population in the gastro-intestinal tract.

Reliability of a multiplex PCR assay for the identification of the major Campylobacter taxa.

The primer pair (C412F/C1228R) constructed previously for the polymerase chain reaction (PCR) identification of the genus Campylobacter using an approximate 800 base pair (bp) 16S rRNA gene target segment proved to be useful for the identification of a total of 49 Campylobacter lari isolates including urease-positive thermophilic Campylobacter (UPTC) organisms (n=25). When the primer pair (CLF/R) developed previously for the PCR identification of C. lari species using an approximate 250 bp glyA segment was employed, 27 C. lari isolates, including all the UPTC isolates, were identified to be PCR-negative (55%). Therefore, this PCR procedure developed for the molecular identification of C. lari was shown to be unreliable for C. lari identification. Nucleotide sequencing analysis clarified the reason(s) why PCR-negative examples occurred in many C. lari isolates, including UPTC isolates. The primer pair target sequences in the C. lari-specific PCR-negative isolates apparently varied at the 3' end region, as compared with C. lari-specific PCR-positive isolates. Thus, the multiplex PCR assay developed previously was shown to be unreliable for the molecular identification of C. lari subspecies organisms.

Age and geographic dependence of Zika virus infection during the outbreak on Yap island, 2007.

Intensive surveillance of Zika virus infection conducted on Yap Island has provided crucial information on the epidemiological characteristics of the virus, but the rate of infection and medical attendance stratified by age and geographical location of the epidemic have yet to be fully clarified. In the present study, we reanalyzed surveillance data reported in a previous study. Likelihood-based Bayesian inference was used to gauge the age and geographically dependent force of infection and age-dependent reporting rate, with unobservable variables imputed by the data augmentation method. The inferred age-dependent component of the force of infection was suggested to be up to 3-4 times higher among older adults than among children. The age-dependent reporting rate ranged from 0.7% (5-9 years old) to 3.3% (50-54 years old). The proportion of serologically confirmed cases among total probable or confirmed cases was estimated to be 44.9%. The cumulative incidence of infection varied by municipality: Median values were over 80% in multiple locations (Gagil, Tomil, and Weloy), but relatively low values (below 50%) were derived in other locations. However, the possibility of a comparably high incidence of infection was not excluded even in municipalities with the lowest estimates. The results suggested a high degree of heterogeneity in the Yap epidemic. The force of infection and reporting rate were higher among older age groups, and this discrepancy implied that the demographic patterns were remarkably different between all infected and medically attended individuals. A higher reporting rate may have reflected more severe clinical presentation among adults. The symptomatic ratio in dengue cases is known to correlate with age, and our findings presumably indicate a similar tendency in Zika virus disease.

Sodium acetate enhances hydrogen peroxide production in Weissella cibaria.

AIMS: To investigate hydrogen peroxide production by lactic acid bacteria (LAB) and to determine the key factors involved. METHODS AND RESULTS: Six strains of Weissella cibaria produced large amounts (2.2-3.2 mmol l(-1)) of hydrogen peroxide in GYP broth supplemented with sodium acetate, but very low accumulations in glucose yeast peptone broth without sodium acetate. Increased production of hydrogen peroxide was also recorded when strains of W. cibaria were cultured in the presence of potassium acetate, sodium isocitrate and sodium citrate. Oxidases and peroxidases were not detected, or were present at low levels in W. cibaria. However, strong nicotinamide adenine dinucleotide (NADH) oxidase activity was recorded, suggesting that the enzyme plays a key role in production of hydrogen peroxide by W. cibaria. CONCLUSIONS: Weissella cibaria produces large quantities of hydrogen peroxide in aerated cultures, in a process that is dependent on the presence of acetate in the culture medium. NADH oxidase is likely the key enzyme in this process. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first study showing that sodium acetate, normally present in culture media of LAB, is a key factor for hydrogen peroxide production by W. cibaria. The exact mechanisms involved are not known.

EVALUATIONS OF INVENTORY AND ACTIVITY CONCENTRATION OF RADIOCESIUM IN SOIL AT A RESIDENTIAL HOUSE 3 YEARS AFTER THE FUKUSHIMA NUCLEAR ACCIDENT.

Soil samples from the surface to a 5 cm depth were collected at a residential house in Koriyama City, Fukushima Prefecture using a scraper plate every three months from March 2014 to September 2014 to evaluate the vertical distribution profiles and inventories of 134Cs and 137Cs in soil. The vertical distribution profiles of radiocesium (134Cs and 137Cs) in soil showed that greater than 86% of the total radiocesium was absorbed in the upper 2 cm 3 years after the accident. Radiocesium in the surface layer seems to move to the lower layer over time. The migration of radiocesium in surface layer might be influenced by the ground surface runoff by rainfall. Radiocesium inventories in June increased significantly over the short period between March and June. In contrast, the radiocesium inventories in September did not increase significantly compared to the values in June. Radiocesium resuspension and deposition caused by decontamination work and meteorological events might be one possible reason for the increased radiocesium inventories observed in June.

Monitoring the bacterial community during fermentation of sunki, an unsalted, fermented vegetable traditional to the Kiso area of Japan.

AIMS: To investigate the microbial community in sunki, an indigenous, unsalted, fermented vegetable, made from the leaves of red beet. METHODS AND RESULTS: Fermenting samples were collected at 1- to 2-day intervals from four houses and investigated by culture-dependent and culture-independent techniques. PCR-Denaturing-Gradient-Gel-Electrophoresis profiles indicated that the bacterial community was stable and Lactobacillus delbrueckii, Lact. fermentum and Lact. plantarum were dominant during the fermentation. This result agreed well with that obtained by the culturing technique. Moulds, yeasts or bacteria other than lactic acid bacteria (LAB) were not detected. CONCLUSIONS: The bacterial community was stable throughout the fermentation, and Lact. delbrueckii, Lact. fermentum and Lact. plantarum were dominant. The acidic pH and lactic acid produced by LAB probably preserve the sunki from spoilage. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report on the use of both culture-dependent and culture-independent techniques to study the bacterial community in sunki. A combination of culture-dependent and culture-independent techniques is necessary for the analysis of complex microbial communities.